1,4,5-substituted 1,2,3-triazole analogues as antagonists of the pregnane X receptor

ABSTRACT

In an aspect, the invention relates to 1,4,5-substituted 1,2,3-triazole and 1,2,4,5-substituted imidazoles, which are modulators the pregnane X receptor (“PXR”); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of modulating an adverse drug reaction in a mammal using the compounds and pharmaceutical compositions; methods of treatment of a disorder of uncontrolled cellular proliferation, such as a cancer, using the compounds and pharmaceutical compositions; methods of modulating pregnane X receptor activity in a mammal using the compounds and pharmaceutical compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a U.S. National Phase Application of International ApplicationNo. PCT/US2017/021949, filed Mar. 10, 2017, which claims the benefit ofU.S. Provisional Application No. 62/313,603, filed Mar. 25, 2016, whichare incorporated herein by reference in their entireties.

BACKGROUND

The pregnane X receptor (PXR) regulates the metabolism and excretion ofxenobiotics and endobiotics by regulating the expression ofdrug-metabolizing enzymes and drug transporters. By affecting drugmetabolism, changes in the expression levels of PXR target genes caninfluence the therapeutic and toxicologic response to drugs and causeadverse drug-drug interactions. The activity of PXR is largely regulatedby direct ligand binding, and the unique structure of PXR allows thebinding of a variety of drugs and prospective drugs. That is, a drug orprospective drug molecule can directly modulate the activity of PXR. Assuch, PXR is associated with multiple undesired drug-drug interactions.

Treatment of multiple diseases and disorders could be improved if therewere available a specific and non-toxic antagonist of PXR is desired. APXR antagonist would be expected to prevent drug-induced adverse drugeffects associated with therapeutic agents that induce the expression ofPXR target genes. In particular, a specific and non-toxic PXR antagonistcould be used as a co-therapeutic agent to prevent therapy-relatedtoxicities, drug-drug interactions, and drug resistance, and improvetherapeutic efficacy and safety. However, due to the “promiscuous”nature of receptor binding (i.e., many drugs bind to and activate PXR)it has been considered extremely difficult to design a PXR antagonistbased on structure, and equally difficult to perform SAR studies. As aresult, there are currently no specific and non-toxic PXR antagonistexists.

Despite in understanding the biochemistry of PXR, there remains a needfor specific and non-toxic antagonists of PXR. These needs and otherneeds are satisfied by the present invention.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in an aspect, relates to1,4,5-substituted 1,2,3-triazole and 1,2,4,5-substituted imidazoles thatare useful as antagonists of the pregnane X receptor (“PXR”). In afurther aspect, the disclosed compounds are useful for modulating anadverse drug reaction in a mammal. In a still further aspect, thedisclosed compounds are useful for treatment of a disorder ofuncontrolled cellular proliferation, such as a cancer. In an aspect, thedisclosed compounds can be used for treatment of a disorder ofuncontrolled cellular proliferation alone or in combination with eitheran anticancer agent or a treatment scheme using a combination ofmultiple anticancer agents. In a yet further aspect, the disclosedcompounds are useful for modulating pregnane X receptor activity in amammal.

Disclosed are compounds having a structure represented by a formula:

wherein L is SO₂, C═O. or NR¹⁰; wherein R¹⁰ is hydrogen or C1-C3 alkyl;wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen or halogen; wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ ishydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—OH, —(C1-C6alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ is monocyclic arylor monocyclic heteroaryl substituted with 0, 1, 2, or 3 groups selectedfrom halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl,C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹ is C3-C8cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof, and wherein the compound doesnot have the structure:

Also disclosed are compounds having a structure represented by aformula:

wherein L is C═O or NR¹⁰; wherein R¹⁰ is hydrogen or C1-C3 alkyl;wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ ishydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—OH, —(C1-C6alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ is monocyclic arylor monocyclic heteraryl substituted with 0, 1, 2, or 3 groups selectedfrom halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl,C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹ is C3-C8cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein L is SO₂, C═O, or NR¹⁰; wherein R¹⁰ is hydrogen or C1-C3 alkyl;wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; wherein R¹¹ ishydrogen or C1-C6 alkyl; wherein R¹² is hydrogen, cyano, halogen, C1-C6alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6 alkyl),—(C═O)—O(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—OH, —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹;wherein Ar¹ is monocyclic aryl or monocyclic heteraryl substituted with0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino, C1-C3alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;wherein Cy¹ is C3-C8 cycloalkyl or C2-C7 heterocycloalkyl substitutedwith 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino,C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3polyhaloalkyl; or a pharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ ishydrogen, cyano, halogen, C2-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, orCy¹; wherein Ar¹ is monocyclic aryl or monocyclic heteraryl substitutedwith 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino,C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3polyhaloalkyl; wherein Cy¹ is C3-C8 cycloalkyl or C2-C7 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy,cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, orC1-C3 polyhaloalkyl; wherein R⁵ is hydrogen, halogen, hydroxy, C1-C3alkyl; wherein R⁶ is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁷is C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy,C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H, —(C═O)—(C1-C6alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy, halogen, C1-C6alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ is hydrogen, cyano,halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6alkyl), —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ ismonocyclic aryl or monocyclic heteraryl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹is C3-C8 cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2,or 3 groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl,C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; whereinR⁵ is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ ishydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, orCy¹; wherein Ar¹ is monocyclic aryl or monocyclic heteraryl substitutedwith 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino,C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3polyhaloalkyl; wherein Cy¹ is C3-C8 cycloalkyl or C2-C7 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy,cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, orC1-C3 polyhaloalkyl; wherein R⁵ is hydrogen, halogen, hydroxy, C1-C3alkyl; wherein R⁶ is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein atleast one of R⁵ or R⁶ is not hydrogen; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein at leastone of R¹ or R³ is hydroxy; wherein R⁴ is hydrogen, cyano, halogen,C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl),—(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ ismonocyclic aryl or monocyclic heteraryl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹is C3-C8 cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2,or 3 groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl,C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; whereinR⁵ is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a disclosed compound or a product ofa disclosed method of making and a pharmaceutically acceptable carrier.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a compound having a structurerepresented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.

Also disclosed are methods for modulating an adverse drug reaction in amammal comprising the step of administering to the mammal atherapeutically effective amount of at least one disclosed compound; adisclosed pharmaceutical composition; or a compound having a structurerepresented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are methods for treatment of a disorder of uncontrolledcellular proliferation in a mammal comprising the step of administeringto the mammal a therapeutically effective amount of at least onedisclosed compound; a disclosed pharmaceutical composition; or acompound having a structure represented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are methods for modulating pregnane X receptor activityin a mammal comprising the step of administering to the mammal atherapeutically effective amount of at least disclosed compound; adisclosed pharmaceutical composition; or a compound having a structurerepresented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are methods for modulating pregnane X receptor activityin at least one cell, comprising the step of contacting the at least onecell with an effective amount of at least one disclosed compound; adisclosed pharmaceutical composition; or a compound having a structurerepresented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are kits comprising at least disclosed one compound; adisclosed pharmaceutical composition; or a compound having a structurerepresented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof; and one or more of: (a) atleast one agent known to increase pregnane X receptor activity; (b) atleast one agent known to decrease pregnane X receptor activity; (c) atleast one agent known to treat a disorder of uncontrolled cellularproliferation; (d) at least one agent known to treat an infectiousdisease; (e) at least one agent known to be a non-steroidalanti-inflammatory drug; (f) at least one agent known to be ananti-convulsant agent; or (g) instructions for treating a disorderassociated with pregnane X receptor dysfunction.

Also disclosed are methods for the manufacturing a medicament comprisingcombining at least one disclosed compound or at least one disclosedproduct with a pharmaceutically acceptable carrier or diluent.

Also disclosed are uses of a disclosed compound or a disclosed productin the manufacture of a medicament for modulating an adverse drugreaction in a mammal.

Also disclosed are uses of a disclosed compound or a disclosed productin the manufacture of a medicament for treatment of a disorder ofuncontrolled cellular proliferation in a mammal.

Also disclosed are uses of a disclosed compound or a disclosed productin the manufacture of a medicament for modulating pregnane X receptoractivity in a mammal comprising the step of administering to the mammal.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIGS. 1A-1D show representative data for a representative disclosedcompound showing that the tested compound modulates the activity of anhPXR agonist in primary human hepatocytes (“PHHs”). The test compoundused in these studies was4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole,and the structure is shown in FIG. 1D (herein referred to as the “testcompound”). PHHs were pretreated with DMSO (0.1%), 1.6 μM of rifampicin(RIF), 0.5 μM of paclitaxel (PTX) or 5 μM of PTX, respectively, in theabsence and presence of 10 μM of the test compound. After 72 hr, PHHsthen received 3.3 μM of midazolam (MDZ) treatment for 4 h. Theconcentrations of 1′-OH MDZ (MDZ metabolite) in the media of eachpretreatment condition were determined using LC/MS/MS as described inthe Examples. The results are shown in FIG. 1A, and the data show thatmetabolism of MDZ is essentially blocked in the presence of the testcompound regardless of the pretreatment condition. PHHs were alsotreated with 1 μM of PTX in the absence and presence of 10 μM of thetest compound, and then the concentrations of major PTX metabolites,3-OH PTX (by CYP3A4) and 6α-OH PTX (by CYP2C8), were determined usingLC/MS/MS at 24 hr and 48 hr of treatment, respectively. Theconcentrations of 3-OH PTX and 6α-OH PTX are shown in FIGS. 1B and 1C,respectively. The data show that at both 24 and 48 hr of treatment themetabolism of PTX to either of the metabolites examined, 3-OH PTX and6α-OH PTX, was effectively blocked by treatment with the test compound.

FIGS. 2A-2D show representative data for a representative disclosedcompound showing that the tested compound sensitizes colon cancer cellsto representative anti-cancer drugs. The test compound used in thesestudies was4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole,and the structure is shown in FIG. 1D (herein referred to as the “testcompound”). LS 180 cells stably overexpressed hPXR were treated withserial dilutions of paclitaxel (PTX; see FIG. 2A), docetaxel (TXT; seeFIG. 2B), vinblastine (VBL; see FIG. 2C), or vincristine (VCR; see FIG.2D) in the absence and presence of 10 μM of the test compound asindicated for 96 h. Values of the viability of compound-treated cellswere expressed as a percentage of that of DMSO-treated cells, and drugconcentration is expressed in a log scale. Data at each point representsmean±SEM from quadruplicate measurements. The data shown in FIGS. 2A-2Dshow that the apparent IC₅₀ for PTX, TXT, VBL, or VCR is significantlyhigher in the absence of the test compound.

FIGS. 3A-3C show representative data for a representative disclosedcompound showing that the tested compound inhibits the hPXR-mediatedincrease in CYP3A expression. The test compound used in these studieswas4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole,and the structure is shown in FIG. 1D (herein referred to as the “testcompound”). FIG. 3A shows data for the expression levels of liverCyp3a11 mRNA in the mouse model. Briefly, mouse liver Cyp3a11 mRNA wasanalyzed by real-time PCR in hPXR-tg mice treated with vehicle control(Vehicle), RIF (10 mg/kg) or RIF (10 mg/kg) plus test compound (200mg/kg) for 72 h. The liver CYP3A protein levels were also determined byWestern blotting in hPXR-tg mice with the treatments indicated in FIG.3A. Each data point represents the level of Cyp3a11 mRNA (FIG. 3A) orprotein (FIG. 3B) in an individual mouse; lines indicate the mean valuefor 3-7 mice per group. Representative Western blots from 3-5 mice ineach group are shown in FIG. 3C.

FIG. 4 shows representative data for a representative disclosed compoundshowing that the tested compound inhibits the hPXR-mediated increase inCYP3A expression. The test compound used in this study was4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole,and the structure is shown in FIG. 1D (herein referred to as the “testcompound”). The hPXR-CYP3A4-luc reporter mice (n=15) were generated bythe hydrodynamic injection of the pGL3-CYP3A4-luc reporter incombination with pcDNA3-hPXR. Individual mouse received 3 rounds ofsequential treatment of vehicle control (Vehicle), RIF (10 mg/kg) andRIF (10 mg/kg) plus the test compound (150 mg/kg) every 24 h for 2 days,respectively, with a washout period of 72-hour between two rounds oftreatment. The luciferase activity in these reporter mice was recordedby bioluminescence imaging 10 h after the last treatment of each round,and the induction of CYP3A4 promoter reporter activity was calculated asdescribed in Examples. Each data point represents the induction ofCYP3A4 promoter reporter activity by the treatment in an individualmouse, and dos lines indicate the CYP3A4 promoter reporter activitychange in individual mouse after following round of treatment. p valuesare indicated between the two treatment compared by paired t test. Thedata show the RIF-induced expression of the reporter under the controlof the CYP3A4 promoter is significantly reduced when treatment with RIFoccurs in the presence of the test compound.

FIG. 5 shows representative data for a representative disclosed compoundshowing that the tested compound modulates effects of the anesthetic(2,2,2-tribromoethanolamine) in hPXR transgenic mice. The test compoundused in this study was4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole,and the structure is shown in FIG. 1D (herein referred to as the “testcompound”). Loss of righting reflex (LORR) duration was recorded asdescribed in Examples to measure metabolism of the anesthetic(2,2,2-tribromoethanolamine) in hPXR-tg, mice before and after treatmentwith vehicle, RIF, and RIF plus the test compound as indicated. Eachdata point represents LORR duration in an individual mouse; linesindicate LORR duration change in individual mouse before and aftertreatment. P values indicate comparison of values by paired t test. Thedata show that the apparent RIF-induced metabolism of the anesthetic(2,2,2-tribromoethanolamine), as determined by measurement of LORR, issignificantly inhibited by treatment of mice in the presence of the testcompound.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. Definitions

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. When one or more stereochemical features are present,Cahn-Ingold-Prelog rules for stereochemistry can be employed todesignate stereochemical priority, E/Z specification, and the like. Oneof skill in the art can readily ascertain the structure of a compound ifgiven a name, either by systemic reduction of the compound structureusing naming conventions, or by commercially available software, such asCHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

As used in the specification and in the claims, the term “comprising”can include the aspects “consisting of” and “consisting essentially of.”Thus, for example, an aspect such as “a composition comprising A, B, andC” also includes aspects such as “a composition consisting of A, B, andC” and “a composition consisting essentially of A, B, and C.”

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

As used herein, the terms “about,” “approximate,” and “at or about” meanthat the amount or value in question can be the exact value designatedor a value that provides equivalent results or effects as recited in theclaims or taught herein. That is, it is understood that amounts, sizes,formulations, parameters, and other quantities and characteristics arenot and need not be exact, but may be approximate and/or larger orsmaller, as desired, reflecting tolerances, conversion factors, roundingoff, measurement error and the like, and other factors known to those ofskill in the art such that equivalent results or effects are obtained.In some circumstances, the value that provides equivalent results oreffects cannot be reasonably determined. In such cases, it is generallyunderstood, as used herein, that “about” and “at or about” mean thenominal value indicated ±10% variation unless otherwise indicated orinferred. In general, an amount, size, formulation, parameter or otherquantity or characteristic is “about,” “approximate,” or “at or about”whether or not expressly stated to be such. It is understood that where“about,” “approximate,” or “at or about” is used before a quantitativevalue, the parameter also includes the specific quantitative valueitself, unless specifically stated otherwise.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or can not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the terms “PXR” and “pregnane X receptor” can be usedinterchangeably and refer to a nuclear receptor protein encoded by theNR1I2 gene, which is a transcriptional regulator of cytochrome P450genes such as CYP3A4 and CYP3A5. PXR has a human gene map locus given as3q12-q13.3, 3q13.3, and 3q12-q13.3 by Entrez Gene, Ensembl, and HGNC,respectively. The corresponding rat and mouse genes are given the genesymbol Nr1i2, and the respective gene map loci are 11q21 and 16 B3. Thegene and protein have variously been referred to in the scientificliterature as ONR1, BXR, SXR, PAR2, Orphan nuclear receptor PAR1,pregnane-activated receptor, steroid and xenobiotic receptor, MGC108643,pregnane X receptor (nuclear receptor sub family 1, group I, member 2),nuclear receptor subfamily 1 group I member 2, NR1I2, orphan nuclearreceptor PXR, PXR.1, PXR.2, mPXR, and nuclear receptor subfamily 1,group 1, member 2. It can be appreciated that these terms can also beused to refer to PXR. The term PXR is understood to be inclusive ofrelated homologous proteins in other species. The human form can bespecifically designated by the term “hPXR.” The PXR protein ischaracterized by a DNA binding domain and a ligand binding domain (alsoreferred to by the term “LBD”). The PXR protein forms a heterodimer withthe 9-cis retinoic acid receptor RXR, and the formation of theheterodimer is required for transcriptional activation of target genes,and the heterodimer binds to the response element of the CYP3A4 orCYP3A5 promoter. The heterodimer is also believed to bind to theresponse elements of the ABCB1/MDR1 gene.

The major human, rat, and mouse PXR protein isoforms encoded by the PXRgene (NR1I2) are, respectively, 434, 431, and 431 amino acids. However,several major splice variants have been described at least for humanencoding different isoforms, some of which have been described as usingnon-AUG translation initiation codons. For example, a significant humanisoform is the “long isoform”, that is 473 amino acids comprising 39additional amino acids added to the N-terminus of the major humanisoform which is 434 amino acids. The LBD of the major human isoform isfrom amino acids 141-434, whereas the LBD of the long isoform is fromamino acids 180-473.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In an aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects.

In some aspects of the disclosed methods, the subject has been diagnosedwith a need for treatment of an infectious disease prior to theadministering step. In some aspects of the disclosed methods, thesubject has been diagnosed with a need for modulating PXR activity priorto the administering step. In some aspects of the disclosed methods, thesubject has been diagnosed with having a gram positive or gram negativeinfection prior to the administering step. In some aspects of thedisclosed methods, the subject has been identified with an infectiousdisease that is treatable by antagonizing the activity of PXR prior tothe administering step. In some aspects of the disclosed methods, thesubject has been identified with a gram positive bacterial infectionprior to the administering step. In various aspects of the disclosedmethods, the subject has been identified with a gram negative bacterialinfection prior to the administering step. In an aspect, a subject canbe treated prophylactically with a compound or composition disclosedherein, as discussed herein elsewhere.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In an aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein. For example,“diagnosed with an infectious disease treatable by antagonizing PXRactivity” means having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditionthat can be diagnosed or treated by a compound or composition that caninhibit PXR activity. As a further example, “diagnosed with a need fortreatment of an infectious disease” refers to having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition characterized by infection with a pathogenicmicrobe, such as a gram positive or gram negative bacteria.

As used herein, the phrase “identified to be in need of treatment for aninfectious disease,” or the like, refers to selection of a subject basedupon need for treatment of the infectious disease. For example, asubject can be identified as having a need for treatment of aninfectious disease (e.g., an infectious disease related to infectionwith a pathogenic gram negative or gram positive bacteria) based upon anearlier diagnosis by a person of skill and thereafter subjected totreatment for the infectious disease. It is contemplated that theidentification can, In an aspect, be performed by a person differentfrom the person making the diagnosis. It is also contemplated, in afurther aspect, that the administration can be performed by one whosubsequently performed the administration.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

The term “contacting” as used herein refers to bringing a disclosedcompound and a cell, a target protein (e.g. the PXR protein), or otherbiological entity together in such a manner that the compound can affectthe activity of the target, either directly; i.e., by interacting withthe target itself, or indirectly; i.e., by interacting with anothermolecule, co-factor, factor, or protein on which the activity of thetarget is dependent.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side effects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “kit” means a collection of at least two componentsconstituting the kit. Together, the components constitute a functionalunit for a given purpose. Individual member components may be physicallypackaged together or separately. For example, a kit comprising aninstruction for using the kit may or may not physically include theinstruction with other individual member components. Instead, theinstruction can be supplied as a separate member component, either in apaper form or an electronic form which may be supplied on computerreadable memory device or downloaded from an internet website, or asrecorded presentation.

As used herein, “instruction(s)” means documents describing relevantmaterials or methodologies pertaining to a kit. These materials mayinclude any combination of the following: background information, listof components and their availability information (purchase information,etc.), brief or detailed protocols for using the kit, trouble-shooting,references, technical support, and any other related documents.Instructions can be supplied with the kit or as a separate membercomponent, either as a paper form or an electronic form which may besupplied on computer readable memory device or downloaded from aninternet website, or as recorded presentation. Instructions can compriseone or multiple documents, and are meant to include future updates.

As used herein, the terms “therapeutic agent” include any synthetic ornaturally occurring biologically active compound or composition ofmatter which, when administered to an organism (human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. The term thereforeencompasses those compounds or chemicals traditionally regarded asdrugs, vaccines, and biopharmaceuticals including molecules such asproteins, peptides, hormones, nucleic acids, gene constructs and thelike. Examples of therapeutic agents are described in well-knownliterature references such as the Merck Index (14th edition), thePhysicians' Desk Reference (64th edition), and The Pharmacological Basisof Therapeutics (12th edition), and they include, without limitation,medicaments; vitamins; mineral supplements; substances used for thetreatment, prevention, diagnosis, cure or mitigation of a disease orillness; substances that affect the structure or function of the body,or pro-drugs, which become biologically active or more active after theyhave been placed in a physiological environment. For example, the term“therapeutic agent” includes compounds or compositions for use in all ofthe major therapeutic areas including, but not limited to, adjuvants;anti-infectives such as antibiotics and antiviral agents; analgesics andanalgesic combinations, anorexics, anti-inflammatory agents,anti-epileptics, local and general anesthetics, hypnotics, sedatives,antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics,antagonists, neuron blocking agents, anticholinergic and cholinomimeticagents, antimuscarinic and muscarinic agents, antiadrenergics,antiarrhythmics, antihypertensive agents, hormones, and nutrients,antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines,antinauseants, antineoplastics, antipruritics, antipyretics;antispasmodics, cardiovascular preparations (including calcium channelblockers, beta-blockers, beta-agonists and antiarrythmics),antihypertensives, diuretics, vasodilators; central nervous systemstimulants; cough and cold preparations; decongestants; diagnostics;hormones; bone growth stimulants and bone resorption inhibitors;immunosuppressives; muscle relaxants; psychostimulants; sedatives;tranquilizers; proteins, peptides, and fragments thereof (whethernaturally occurring, chemically synthesized or recombinantly produced);and nucleic acid molecules (polymeric forms of two or more nucleotides,either ribonucleotides (RNA) or deoxyribonucleotides (DNA) includingboth double- and single-stranded molecules, gene constructs, expressionvectors, antisense molecules and the like), small molecules (e.g.,doxorubicin) and other biologically active macromolecules such as, forexample, proteins and enzymes. The agent may be a biologically activeagent used in medical, including veterinary, applications and inagriculture, such as with plants, as well as other areas. The termtherapeutic agent also includes without limitation, medicaments;vitamins; mineral supplements; substances used for the treatment,prevention, diagnosis, cure or mitigation of disease or illness; orsubstances which affect the structure or function of the body; orpro-drugs, which become biologically active or more active after theyhave been placed in a predetermined physiological environment.

As used herein, “EC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%activation or enhancement of a biological process, or component of aprocess. For example, EC₅₀ can refer to the concentration of a compoundthat provokes a response halfway between the baseline and maximumresponse in an appropriate assay of the target activity. For example, anEC₅₀ for the PXR can be determined in an in vitro assay system. Such invitro assay systems include assay such as the assays as describedherein.

As used herein, “IC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process, includinga protein, subunit, organelle, ribonucleoprotein, etc. In an aspect, anIC₅₀ can refer to the concentration of a substance that is required for50% inhibition in vivo, as further defined elsewhere herein. In afurther aspect, IC₅₀ refers to the half maximal (50%) inhibitoryconcentration (IC) of a substance. For example, an EC₅₀ for the PXR canbe determined in an in vitro assay system. Such in vitro assay systemsinclude assay such as the assays as described herein.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “aliphatic” or “aliphatic group,” as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spirofusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groupsinclude, but are not limited to, linear or branched, alkyl, alkenyl, andalkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Thealkyl group can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms. The term alkyl group can also bea C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the likeup to and including a C1-C24 alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl”specifically refers to an alkyl group that is substituted with a singlehalide, e.g. fluorine, chlorine, bromine, or iodine. The term“polyhaloalkyl” specifically refers to an alkyl group that isindependently substituted with two or more halides, i.e. each halidesubstituent need not be the same halide as another halide substituent,nor do the multiple instances of a halide substituent need to be on thesame carbon. The term “alkoxyalkyl” specifically refers to an alkylgroup that is substituted with one or more alkoxy groups, as describedbelow. The term “aminoalkyl” specifically refers to an alkyl group thatis substituted with one or more amino groups. The term “hydroxyalkyl”specifically refers to an alkyl group that is substituted with one ormore hydroxy groups. When “alkyl” is used in one instance and a specificterm such as “hydroxyalkyl” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“hydroxyalkyl” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula —(CH₂)_(a)—, where “a” is an integer of from2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² or—OA¹-(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A2)C═C(A³A4)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aromatic group” as used herein refers to a ring structurehaving cyclic clouds of delocalized π electrons above and below theplane of the molecule, where the it clouds contain (4n+2) π electrons. Afurther discussion of aromaticity is found in Morrison and Boyd, OrganicChemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages477-497, incorporated herein by reference. The term “aromatic group” isinclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, anthracene, and the like. The aryl group can besubstituted or unsubstituted. The aryl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, —NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in thedefinition of “aryl.” In addition, the aryl group can be a single ringstructure or comprise multiple ring structures that are either fusedring structures or attached via one or more bridging groups such as acarbon-carbon bond. For example, biaryl to two aryl groups that arebound together via a fused ring structure, as in naphthalene, or areattached via one or more carbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein. A specific example of amino is—NH₂.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula-(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a), where A¹ and A² canbe, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group described herein and “a” is aninteger from 1 to 500. “Polyester” is as the term used to describe agroup that is produced by the reaction between a compound having atleast two carboxylic acid groups with a compound having at least twohydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula -(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The terms “halo,” “halogen” or “halide,” as used herein can be usedinterchangeably and refer to F, Cl, Br, or I.

The terms “pseudohalide,” “pseudohalogen” or “pseudohalo,” as usedherein can be used interchangeably and refer to functional groups thatbehave substantially similar to halides. Such functional groups include,by way of example, cyano, thiocyanato, azido, trifluoromethyl,trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

The term “heteroalkyl” as used herein refers to an alkyl groupcontaining at least one heteroatom. Suitable heteroatoms include, butare not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorousand sulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quaternized. Heteroalkyls can be substituted as defined abovefor alkyl groups.

The term “heteroaryl” as used herein refers to an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. The heteroarylgroup can be substituted or unsubstituted. The heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein. Heteroaryl groups can bemonocyclic, or alternatively fused ring systems. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl,isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl,benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl,benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, andpyrazolopyrimidinyl. Further not limiting examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, andpyrido[2,3-b]pyrazinyl.

The terms “heterocycle” or “heterocyclyl,” as used herein can be usedinterchangeably and refer to single and multi-cyclic aromatic ornon-aromatic ring systems in which at least one of the ring members isother than carbon. Thus, the term is inclusive of, but not limited to,“heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and“polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine,furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole,thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole,1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including,1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole,including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine,including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine,azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. Theterm heterocyclyl group can also be a C2 heterocyclyl, C2-C3heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like upto and including a C2-C18 heterocyclyl. For example, a C2 heterocyclylcomprises a group which has two carbon atoms and at least oneheteroatom, including, but not limited to, aziridinyl, diazetidinyl,dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, forexample, a C5 heterocyclyl comprises a group which has five carbon atomsand at least one heteroatom, including, but not limited to, piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and thelike. It is understood that a heterocyclyl group may be bound eitherthrough a heteroatom in the ring, where chemically possible, or one ofcarbons comprising the heterocyclyl ring.

The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as usedherein refers to a ring system in which at least one of the ring membersis other than carbon. Bicyclic heterocyclyl encompasses ring systemswherein an aromatic ring is fused with another aromatic ring, or whereinan aromatic ring is fused with a non-aromatic ring. Bicyclicheterocyclyl encompasses ring systems wherein a benzene ring is fused toa 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms orwherein a pyridine ring is fused to a 5- or a 6-membered ring containing1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, butare not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl,benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl,1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and1H-pyrazolo[3,2-b]pyridin-3-yl.

The term “heterocycloalkyl” as used herein refers to an aliphatic,partially unsaturated or fully saturated, 3- to 14-membered ring system,including single rings of 3 to 8 atoms and bi- and tricyclic ringsystems. The heterocycloalkyl ring-systems include one to fourheteroatoms independently selected from oxygen, nitrogen, and sulfur,wherein a nitrogen and sulfur heteroatom optionally can be oxidized anda nitrogen heteroatom optionally can be substituted. Representativeheterocycloalkyl groups include, but are not limited to, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “hydroxyl” or “hydroxy” as used herein is represented by theformula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” or “azido” as used herein is represented by the formula—N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” or “cyano” as used herein is represented by theformula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” . . . “R^(n),” where n is an integer, as used hereincan, independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(α))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘); —C(NOR)R^(∘);—(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘);—(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘);—N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘);—C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘) ₂;—OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(∘) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, and brosylate.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has thestructure:

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthylradical. In some embodiments, an organic radical can contain 1-10inorganic heteroatoms bound thereto or therein, including halogens,oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organicradicals include but are not limited to an alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, mono-substituted amino,di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl,substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclicradicals, wherein the terms are defined elsewhere herein. A fewnon-limiting examples of organic radicals that include heteroatomsinclude alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals,dimethylamino radicals and the like.

“Inorganic radicals,” as the term is defined and used herein, contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have 10 or fewer, or preferably one tosix or one to four inorganic atoms as listed above bonded together.Examples of inorganic radicals include, but not limited to, amino,hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonlyknown inorganic radicals. The inorganic radicals do not have bondedtherein the metallic elements of the periodic table (such as the alkalimetals, alkaline earth metals, transition metals, lanthanide metals, oractinide metals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Inorganicradicals do not comprise metalloids elements such as boron, aluminum,gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gaselements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Inglod-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labeled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, suchas ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, and ³⁶C1, respectively.Compounds further comprise prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labeled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labeled compounds of the presentinvention and prodrugs thereof can generally be prepared by carrying outthe procedures below, by substituting a readily available isotopicallylabeled reagent for a non-isotopically labeled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvent orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. Unless stated to the contrary, theinvention includes all such possible tautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), and R^(n(e)). By “independent substituents,” it is meant thateach R substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplemental Volumes (Elsevier Science Publishers, 1989); OrganicReactions, Volumes 1-40 (John Wiley and Sons, 1991); March's AdvancedOrganic Chemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds cannot be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. Compounds

In an aspect, disclosed are compounds useful as antagonists of thepregnane X receptor (“PXR”). In a further aspect, the disclosedcompounds are useful for modulating an adverse drug reaction in amammal. In a still further aspect, the disclosed compounds are usefulfor treatment of a disorder of uncontrolled cellular proliferation, suchas a cancer. In an aspect, the disclosed compounds can be used fortreatment of a disorder of uncontrolled cellular proliferation alone orin combination with an anticancer agent or a treatment scheme using acombination of multiple anticancer agents. In a yet further aspect, thedisclosed compounds are useful for modulating pregnane X receptoractivity in a mammal.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In an aspect, disclosed are compounds having a structure represented bya formula:

wherein L is SO₂, C═O. or NR¹⁰; wherein R¹⁰ is hydrogen or C1-C3 alkyl;wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen or halogen; wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ ishydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—OH, —(C1-C6alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ is monocyclic arylor monocyclic heteraryl substituted with 0, 1, 2, or 3 groups selectedfrom halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl,C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹ is C3-C8cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof; and wherein the compound doesnot have the structure:

Also disclosed are compounds having a structure represented by aformula:

wherein L is C═O or NR¹⁰; wherein R¹⁰ is hydrogen or C1-C3 alkyl;wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ ishydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—OH, —(C1-C6alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ is monocyclic arylor monocyclic heteraryl substituted with 0, 1, 2, or 3 groups selectedfrom halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl,C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹ is C3-C8cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ ishydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—OH, —(C1-C6alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ is monocyclic arylor monocyclic heteraryl substituted with 0, 1, 2, or 3 groups selectedfrom halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl,C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹ is C3-C8cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy;wherein R² is hydrogen, fluoro, or methyl; wherein R³ is hydroxy,halogen, methyl, ethyl, methoxy, or ethoxy; wherein R⁴ is fluoro,chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, —CH₂F, —CH₂Cl,—(C═O)CH₃, or —CH₂(C═O)OCH₃, wherein R⁵ is hydrogen, hydroxy, or methyl;wherein R⁶ is hydrogen, hydroxy, or methyl; and wherein R⁷ is propyl,isopropyl, n-butyl, tert-butyl, or sec-butyl.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ ishydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—OH, —(C1-C6alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ is monocyclic arylor monocyclic heteraryl substituted with 0, 1, 2, or 3 groups selectedfrom halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl,C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹ is C3-C8cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; and whereinR¹⁰ is hydrogen or C1-C3 alkyl; or a pharmaceutically acceptable saltthereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy;wherein R² is hydrogen, fluoro, or methyl; wherein R³ is hydroxy,halogen, methyl, ethyl, methoxy, or ethoxy; wherein R⁴ is fluoro,chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, —CH₂F, —CH₂Cl,—(C═O)CH₃, or —CH₂(C═O)OCH₃, wherein R⁵ is hydrogen, hydroxy, or methyl;wherein R⁶ is hydrogen, hydroxy, or methyl; wherein R⁷ is propyl,isopropyl, n-butyl, tert-butyl, or sec-butyl; and wherein R¹⁰ ishydrogen or methyl.

Also disclosed are compounds having a structure represented by aformula:

wherein L is SO₂, C═O, or NR¹⁰; wherein R¹⁰ is hydrogen or C1-C3 alkyl;wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; wherein R¹¹ ishydrogen or C1-C6 alkyl; and wherein R¹² is hydrogen, cyano, halogen,C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl),—(C1-C6 alkyl)-(C═O)—OH, —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, orCy¹; wherein Ar¹ is monocyclic aryl or monocyclic heteraryl substitutedwith 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino,C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3polyhaloalkyl; wherein Cy¹ is C3-C8 cycloalkyl or C2-C7 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy,cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, orC1-C3 polyhaloalkyl; or a pharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; wherein R¹⁰ ishydrogen or C1-C3 alkyl; wherein R¹¹ is hydrogen or C1-C6 alkyl; andwherein R¹² is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—OH,—(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ ismonocyclic aryl or monocyclic heteraryl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹is C3-C8 cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2,or 3 groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl,C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy;wherein R² is hydrogen, fluoro, or methyl; wherein R³ is hydroxy,halogen, methyl, ethyl, methoxy, or ethoxy; wherein R⁵ is hydrogen,hydroxy, or methyl; wherein R⁶ is hydrogen, hydroxy, or methyl; whereinR⁷ is propyl, isopropyl, n-butyl, tert-butyl, or sec-butyl; wherein R¹⁰is hydrogen or methyl; wherein R¹¹ is hydrogen or methyl; and whereinR¹² is fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl,—CH₂F, —CH₂Cl, —(C═O)CH₃, or —CH₂(C═O)OCH₃.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; wherein R¹¹ ishydrogen or C1-C6 alkyl; and wherein R¹² is hydrogen, cyano, halogen,C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl),—(C1-C6 alkyl)-(C═O)—OH, —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, orCy¹; wherein Ar¹ is monocyclic aryl or monocyclic heteraryl substitutedwith 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino,C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3polyhaloalkyl; wherein Cy¹ is C3-C8 cycloalkyl or C2-C7 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy,cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, orC1-C3 polyhaloalkyl; or a pharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy;wherein R² is hydrogen, fluoro, or methyl; wherein R³ is hydroxy,halogen, methyl, ethyl, methoxy, or ethoxy; wherein R⁵ is hydrogen,hydroxy, or methyl; wherein R⁶ is hydrogen, hydroxy, or methyl; whereinR⁷ is propyl, isopropyl, n-butyl, tert-butyl, or sec-butyl; wherein R¹¹is hydrogen or methyl; and wherein R¹² is fluoro, chloro, bromo, cyano,methyl, ethyl, propyl, isopropyl, —CH₂F, —CH₂Cl, —(C═O)CH₃, or—CH₂(C═O)OCH₃.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵ ishydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; wherein R¹¹ ishydrogen or C1-C6 alkyl; and wherein R¹² is hydrogen, cyano, halogen,C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl),—(C1-C6 alkyl)-(C═O)—OH, —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, orCy¹; wherein Ar¹ is monocyclic aryl or monocyclic heteraryl substitutedwith 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino,C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3polyhaloalkyl; wherein Cy¹ is C3-C8 cycloalkyl or C2-C7 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy,cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, orC1-C3 polyhaloalkyl; or a pharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy;wherein R² is hydrogen, fluoro, or methyl; wherein R³ is hydroxy,halogen, methyl, ethyl, methoxy, or ethoxy; wherein R⁵ is hydrogen,hydroxy, or methyl; wherein R⁶ is hydrogen, hydroxy, or methyl; whereinR⁷ is propyl, isopropyl, n-butyl, tert-butyl, or sec-butyl; wherein R¹¹is hydrogen or methyl; and wherein R¹² is fluoro, chloro, bromo, cyano,methyl, ethyl, propyl, isopropyl, —CH₂F, —CH₂Cl, —(C═O)CH₃, or—CH₂(C═O)OCH₃.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ ishydrogen, cyano, halogen, C2-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, orCy¹; wherein Ar¹ is monocyclic aryl or monocyclic heteraryl substitutedwith 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino,C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3polyhaloalkyl; wherein Cy¹ is C3-C8 cycloalkyl or C2-C7 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy,cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, orC1-C3 polyhaloalkyl; wherein R⁵ is hydrogen, halogen, hydroxy, C1-C3alkyl; wherein R⁶ is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁷is C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy;wherein R² is hydrogen, fluoro, or methyl; wherein R³ is hydroxy,halogen, methyl, ethyl, methoxy, or ethoxy; wherein R⁴ is fluoro,chloro, bromo, cyano, propyl, isopropyl, —CH₂F, —CH₂Cl, —(C═O)CH₃, or—CH₂(C═O)OCH₃, wherein R⁵ is hydrogen, hydroxy, or methyl; wherein R⁶ ishydrogen, hydroxy, or methyl; and wherein R⁷ is propyl, isopropyl,n-butyl, tert-butyl, or sec-butyl.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy,C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H, —(C═O)—(C1-C6alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy, halogen, C1-C6alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ is hydrogen, cyano,halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6alkyl), —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ ismonocyclic aryl or monocyclic heteraryl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹is C3-C8 cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2,or 3 groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl,C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; whereinR⁵ is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy;wherein R² is fluoro or methyl; wherein R³ is hydroxy, halogen, methyl,ethyl, methoxy, or ethoxy; wherein R⁴ is fluoro, chloro, bromo, cyano,methyl, ethyl, propyl, isopropyl, —CH₂F, —CH₂Cl, —(C═O)CH₃, or—CH₂(C═O)OCH₃, wherein R⁵ is hydrogen, hydroxy, or methyl; wherein R⁶ ishydrogen, hydroxy, or methyl; and wherein R⁷ is propyl, isopropyl,n-butyl, tert-butyl, or sec-butyl.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁴ ishydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, orCy¹; wherein Ar¹ is monocyclic aryl or monocyclic heteraryl substitutedwith 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino,C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3polyhaloalkyl; wherein Cy¹ is C3-C8 cycloalkyl or C2-C7 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy,cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, orC1-C3 polyhaloalkyl; wherein R⁵ is hydrogen, halogen, hydroxy, C1-C3alkyl; wherein R⁶ is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein atleast one of R⁵ or R⁶ is not hydrogen; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy;wherein R² is hydrogen, fluoro, or methyl; wherein R³ is hydroxy,halogen, methyl, ethyl, methoxy, or ethoxy; wherein R⁴ is fluoro,chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, —CH₂F, —CH₂Cl,—(C═O)CH₃, or —CH₂(C═O)OCH₃, wherein R⁵ is hydrogen, hydroxy, or methyl;wherein R⁶ is hydrogen, hydroxy, or methyl; wherein at least one of R⁵or R⁶ is not hydrogen; and wherein R⁷ is propyl, isopropyl, n-butyl,tert-butyl, or sec-butyl.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydroxy,halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein at leastone of R¹ or R³ is hydroxy; wherein R⁴ is hydrogen, cyano, halogen,C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl),—(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹; wherein Ar¹ ismonocyclic aryl or monocyclic heteraryl substituted with 0, 1, 2, or 3groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹is C3-C8 cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2,or 3 groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl,C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; whereinR⁵ is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy;wherein R² is hydrogen, fluoro, or methyl; wherein R³ is hydroxy,halogen, methyl, ethyl, methoxy, or ethoxy; wherein at least one of R¹or R³ is hydroxy; wherein R⁴ is fluoro, chloro, bromo, cyano, methyl,ethyl, propyl, isopropyl, —CH₂F, —CH₂Cl, —(C═O)CH₃, or —CH₂(C═O)OCH₃,wherein R⁵ is hydrogen, hydroxy, or methyl; wherein R⁶ is hydrogen,hydroxy, or methyl; and wherein R⁷ is propyl, isopropyl, n-butyl,tert-butyl, or sec-butyl.

a. L Groups

In an aspect, L is SO₂, C═O, or NR¹⁰. In a further aspect, L is C═O orNR¹⁰. In a still further aspect, L is SO₂ or C═O. In a yet furtheraspect, L is SO₂ or NR¹⁰.

In a further aspect, L is SO₂. In a still further aspect, L is C═O. In ayet further aspect, L is NR¹⁰.

b. R¹ Groups

In an aspect, R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, or—(C1-C6)-OH.

In a further aspect, R¹ is hydroxy, —F, —Cl, —Br, methyl, ethyl, propyl,isopropyl, tert-butyl, sec-butyl, isobutyl, —OCH₃, —OCH₂CH₃,—O(CH₂)₂CH₃, —OCH(CH₃)₂, —(CH₂)—OH, —(CH₂)₂—OH, or —(CH₂)₃—OH. In astill further aspect, R¹ is hydroxy, —F, —Cl, —Br, methyl, —OCH₃, or—(CH₂)—OH.

In a further aspect, R¹ is hydroxy. In a still further aspect, R¹ is —F.In a yet further aspect, R¹ is —Cl. In an even further aspect, R¹ is—Br. In a still further aspect, R¹ is methyl. In a yet further aspect,R¹ is —OCH₃. In an even further aspect, R¹ is —(CH₂)—OH.

In a further aspect, R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy,or —(C1-C6)-OH; and at least one of R¹ or R³ is hydroxy.

In a further aspect, R¹ is hydroxy, —F, —Cl, —Br, methyl, ethyl, propyl,isopropyl, tert-butyl, sec-butyl, isobutyl, —OCH₃, —OCH₂CH₃,—O(CH₂)₂CH₃, —OCH(CH₃)₂, —(CH₂)—OH, —(CH₂)₂—OH, or —(CH₂)₃—OH, and atleast one of R¹ or R³ is hydroxy. In a still further aspect, R¹ ishydroxy, —F, —Cl, —Br, methyl, —OCH₃, or —(CH₂)—OH, and at least one ofR¹ or R³ is hydroxy.

In a further aspect, R¹ is hydroxy, and R³ is hydroxy. In a stillfurther aspect, R¹ is —F, and R³ is hydroxy. In a yet further aspect, R¹is —Cl, and R³ is hydroxy. In an even further aspect, R¹ is —Br, and R³is hydroxy. In a still further aspect, R¹ is methyl, and R³ is hydroxy.In a yet further aspect, R¹ is —OCH₃, and R³ is hydroxy. In an evenfurther aspect, R¹ is —(CH₂)—OH, and R³ is hydroxy.

c. R² Groups

In an aspect, R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy,C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H, —(C═O)—(C1-C6alkyl), or —(C═O)—O(C1-C6 alkyl).

In a further aspect, R² is hydrogen. In a still further aspect, In astill further aspect, R² is hydrogen or halogen. In a yet furtheraspect, R² is halogen.

In a further aspect, R² is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy,C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H, —(C═O)—(C1-C6alkyl), —(C═O)—O(C1-C6 alkyl).

In a further aspect, R² is hydrogen, —F, —Cl, —Br, methyl, ethyl, OCH₃,—OCH₂CH₃, —CHF₂, —CF₃, —CHCl₂, —CCl₃, —CHBr₂, —CBr₃, —CH₂CHF₂, —CH₂CF₃,—CH₂CHCl₂, —CH₂CCl₃, —CH₂CHBr₂, —CH₂CBr₃, —CO₂H, —(C═O)H, —(C═O)CH₃,—(C═O)CH₂CH₃, —(C═O)OCH₃, or —(C═O)OCH₂CH₃. In a still further aspect,R² is hydrogen, —F, —Cl, —Br, methyl, OCH₃, —CHF₂, —CF₃, —CHCl₂, —CCl₃,—CHBr₂, —CBr₃, —CO₂H, —(C═O)H, —(C═O)CH₃, or —(C═O)OCH₃. In a yetfurther aspect, R² is hydrogen, —F, —Cl, —Br, methyl, OCH₃, —CHF₂, —CF₃,—CHCl₂, —CCl₃, —CHBr₂, or —CBr₃. In an even further aspect, R² ishydrogen, —F, —Cl, or —Br, methyl, —F, —Cl, —Br, methyl, OCH₃, —CHF₂,—CF₃, —CHCl₂, —CCl₃, —CHBr₂, or —CBr₃.

In a further aspect, R² is —F, —Cl, —Br, methyl, ethyl, OCH₃, —OCH₂CH₃,—CHF₂, —CF₃, —CHCl₂, —CCl₃, —CHBr₂, —CBr₃, —CH₂CHF₂, —CH₂CF₃, —CH₂CHCl₂,—CH₂CCl₃, —CH₂CHBr₂, —CH₂CBr₃, —CO₂H, —(C═O)H, —(C═O)CH₃, —(C═O)CH₂CH₃,—(C═O)OCH₃, or —(C═O)OCH₂CH₃. In a still further aspect, R² is —F, —Cl,—Br, methyl, OCH₃, —CHF₂, —CF₃, —CHCl₂, —CCl₃, —CHBr₂, —CBr₃, —CO₂H,—(C═O)H, —(C═O)CH₃, or —(C═O)OCH₃. In a yet further aspect, R² is —F,—Cl, —Br, methyl, OCH₃, —CHF₂, —CF₃, —CHCl₂, —CCl₃, —CHBr₂, or —CBr₃. Inan even further aspect, R² is —F, —Cl, or —Br, methyl, —F, —Cl, —Br,methyl, OCH₃, —CHF₂, —CF₃, —CHCl₂, —CCl₃, —CHBr₂, or —CBr₃.

d. R³ Groups

In an aspect, R³ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, or—(C1-C6)-OH.

In a further aspect, R³ is hydroxy, —F, —Cl, —Br, methyl, ethyl, propyl,isopropyl, tert-butyl, sec-butyl, isobutyl, —OCH₃, —OCH₂CH₃,—O(CH₂)₂CH₃, —OCH(CH₃)₂, —(CH₂)—OH, —(CH₂)₂—OH, or —(CH₂)₃—OH. In astill further aspect, R³ is hydroxy, —F, —Cl, —Br, methyl, —OCH₃, or—(CH₂)—OH.

In a further aspect, R³ is hydroxy. In a still further aspect, R³ is —F.In a yet further aspect, R³ is —Cl. In an even further aspect, R³ is—Br. In a still further aspect, R³ is methyl. In a yet further aspect,R³ is —OCH₃. In an even further aspect, R³ is —(CH₂)—OH.

In a further aspect, R³ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy,or —(C1-C6)-OH; and at least one of R¹ or R³ is hydroxy.

In a further aspect, R³ is hydroxy, —F, —Cl, —Br, methyl, ethyl, propyl,isopropyl, tert-butyl, sec-butyl, isobutyl, —OCH₃, —OCH₂CH₃,—O(CH₂)₂CH₃, —OCH(CH₃)₂, —(CH₂)—OH, —(CH₂)₂—OH, or —(CH₂)₃—OH, and atleast one of R¹ or R³ is hydroxy. In a still further aspect, R³ ishydroxy, —F, —Cl, —Br, methyl, —OCH₃, or —(CH₂)—OH, and at least one ofR¹ or R³ is hydroxy.

In a further aspect, R³ is hydroxy, and R¹ is hydroxy. In a stillfurther aspect, R³ is —F, and R¹ is hydroxy. In a yet further aspect, R³is —Cl, and R¹ is hydroxy. In an even further aspect, R³ is —Br, and R¹is hydroxy. In a still further aspect, R³ is methyl, and R¹ is hydroxy.In a yet further aspect, R³ is —OCH₃, and R¹ is hydroxy. In an evenfurther aspect, R³ is —(CH₂)—OH, and R¹ is hydroxy.

e. R⁴ Groups

In an aspect, R⁴ is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—OH,—(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹.

In a further aspect, R⁴ is hydrogen, cyano, halogen, C2-C6 alkyl, C1-C6monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—O(C1-C6alkyl), Ar¹, or Cy¹.

In a further aspect, R⁴ is methyl, ethyl, propyl, isopropyl, n-butyl,tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, ortert-pentyl. In a still further aspect, R⁴ is methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, sec-butyl, or isobutyl. In a yet furtheraspect, R⁴ is methyl, ethyl, propyl, or isopropyl. In an even furtheraspect, R⁴ is methyl or ethyl. In a still further aspect, R⁴ is methyl.

In a further aspect, R⁴ is ethyl, propyl, isopropyl, n-butyl,tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, ortert-pentyl. In a still further aspect, R⁴ is ethyl, propyl, isopropyl,n-butyl, tert-butyl, sec-butyl, or isobutyl. In a yet further aspect, R⁴is ethyl, propyl, or isopropyl. In an even further aspect, R⁴ is ethyl.

In a further aspect, R⁴ is propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, or tert-pentyl.In a still further aspect, R⁴ is propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, or isobutyl. In a yet further aspect, R⁴ is propyl orisopropyl. In an even further aspect, R⁴ is propyl. In a still furtheraspect, R⁴ is isopropyl.

f. R⁵ Groups

In an aspect, R⁵ is hydrogen, halogen, hydroxy, or C1-C3 alkyl. In afurther aspect, R⁵ is hydrogen.

In a further aspect, R⁵ is hydrogen, —F, —Cl, —Br, hydroxy, methyl, orethyl. In a still further aspect, R⁵ is hydrogen, —F, —Cl, —Br, hydroxy,or methyl. In a yet further aspect, R⁵ is hydrogen, —F, —Cl, —Br, orhydroxy. In an even further aspect, R⁵ is hydrogen, hydroxy, methyl, orethyl. In a still further aspect, R⁵ is —F. In a yet further aspect, R⁵is —Cl. In an even further aspect, R⁵ is —Br. In a still further aspect,R⁵ is hydroxy. In a yet further aspect, R⁵ is methyl.

In a further aspect, R⁵ is hydrogen, halogen, hydroxy, C1-C3 alkyl; andat least one of R⁵ or R⁶ is not hydrogen.

In a further aspect, R⁵ is hydrogen, —F, —Cl, —Br, hydroxy, methyl, orethyl; and at least one of R⁵ or R⁶ is not hydrogen. In a still furtheraspect, R⁵ is hydrogen, —F, —Cl, —Br, hydroxy, or methyl; and at leastone of R⁵ or R⁶ is not hydrogen. In a yet further aspect, R⁵ ishydrogen, —F, —Cl, —Br, or hydroxy; and at least one of R⁵ or R⁶ is nothydrogen. In an even further aspect, R⁵ is hydrogen, hydroxy, methyl, orethyl; and at least one of R⁵ or R⁶ is not hydrogen.

In a further aspect, R⁵ is —F, —Cl, —Br, hydroxy, methyl, or ethyl, andR⁶ is hydrogen. In a still further aspect, R⁵ is —F, —Cl, —Br, hydroxy,or methyl, and R⁶ is hydrogen. In a yet further aspect, R⁵—F, —Cl, —Br,or hydroxy, and R⁶ is hydrogen. In an even further aspect, R⁵ ishydroxy, methyl, or ethyl, and R⁶ is hydrogen. In a still furtheraspect, R⁵ is —F, and R⁶ is hydrogen. In a yet further aspect, R⁵ is—Cl, and R⁶ is hydrogen. In an even further aspect, R⁵ is —Br, and R⁶ ishydrogen. In a still further aspect, R⁵ is hydroxy, and R⁶ is hydrogen.In a yet further aspect, R⁵ is methyl, and R⁶ is hydrogen.

g. R⁶ Groups

In an aspect, R⁶ is hydrogen, halogen, hydroxy, or C1-C3 alkyl. In afurther aspect, R⁶ is hydrogen.

In a further aspect, R⁶ is hydrogen, —F, —Cl, —Br, hydroxy, methyl, orethyl. In a still further aspect, R⁶ is hydrogen, —F, —Cl, —Br, hydroxy,or methyl. In a yet further aspect, R⁶ is hydrogen, —F, —Cl, —Br, orhydroxy. In an even further aspect, R⁶ is hydrogen, hydroxy, methyl, orethyl. In a still further aspect, R⁶ is —F. In a yet further aspect, R⁶is —Cl. In an even further aspect, R⁶ is —Br. In a still further aspect,R⁶ is hydroxy. In a yet further aspect, R⁶ is methyl.

In a further aspect, R⁶ is hydrogen, halogen, hydroxy, C1-C3 alkyl; andat least one of R⁶ or R⁶ is not hydrogen.

In a further aspect, R⁶ is hydrogen, —F, —Cl, —Br, hydroxy, methyl, orethyl; and at least one of R⁶ or R⁶ is not hydrogen. In a still furtheraspect, R⁶ is hydrogen, —F, —Cl, —Br, hydroxy, or methyl; and at leastone of R⁶ or R⁶ is not hydrogen. In a yet further aspect, R⁶ ishydrogen, —F, —Cl, —Br, or hydroxy; and at least one of R⁶ or R⁶ is nothydrogen. In an even further aspect, R⁶ is hydrogen, hydroxy, methyl, orethyl; and at least one of R⁶ or R⁶ is not hydrogen.

In a further aspect, R⁶ is —F, —Cl, —Br, hydroxy, methyl, or ethyl, andR⁵ is hydrogen. In a still further aspect, R⁶ is —F, —Cl, —Br, hydroxy,or methyl, and R⁵ is hydrogen. In a yet further aspect, R⁶—F, —Cl, —Br,or hydroxy, and R⁵ is hydrogen. In an even further aspect, R⁶ ishydroxy, methyl, or ethyl, and R⁵ is hydrogen. In a still furtheraspect, R⁶ is —F, and R⁵ is hydrogen. In a yet further aspect, R⁶ is—Cl, and R⁵ is hydrogen. In an even further aspect, R⁶ is —Br, and R⁶ ishydrogen. In a still further aspect, R⁶ is hydroxy, and R⁵ is hydrogen.In a yet further aspect, R⁶ is methyl, and R⁵ is hydrogen.

h. R⁷ Groups

In an aspect, R⁷ is C1-C6 alkyl. In a further aspect, R⁷ is methyl,ethyl, propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl,neopentyl, isopentyl, sec-pentyl, or tert-pentyl. In a still furtheraspect, R⁷ is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, or isobutyl.

In a further aspect, R⁷ is n-butyl, tert-butyl, sec-butyl, or isobutyl.In a still further aspect, R⁷ is n-butyl. In a yet further aspect, R⁷ istert-butyl. In an even further aspect, R⁷ is sec-butyl. In a stillfurther aspect, R⁷ is isobutyl.

In a further aspect, R⁷ is methyl. In a still further aspect, R⁷ isethyl. In a yet further aspect, R⁷ is propyl. In an even further aspect,R⁷ is isopropyl. In a still further aspect, R⁷ is propyl or isopropyl.In a yet further aspect, R⁷ is isopropyl or tert-butyl.

i. R¹⁰ Groups

In an aspect, R¹⁰ is hydrogen or C1-C3 alkyl. In a further aspect, R¹⁰is hydrogen or methyl. In a still further aspect, R¹⁰ is hydrogen. In ayet further aspect, R¹⁰ is methyl.

j. R¹¹ Groups

In an aspect, R¹¹ is hydrogen or C1-C6 alkyl. In a further aspect, R¹¹is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, or tert-pentyl.In a still further aspect, R¹¹ is hydrogen, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, sec-butyl, or isobutyl.

In a further aspect, R¹¹ is hydrogen, n-butyl, tert-butyl, sec-butyl, orisobutyl. In a still further aspect, R¹¹ is hydrogen or n-butyl. In ayet further aspect, R¹¹ is hydrogen or tert-butyl. In an even furtheraspect, R¹¹ is hydrogen or sec-butyl. In a still further aspect, R¹¹ ishydrogen or isobutyl.

In a further aspect, R¹¹ is hydrogen or methyl. In a still furtheraspect, R¹¹ is hydrogen or ethyl. In a yet further aspect, R¹¹ ishydrogen or propyl. In an even further aspect, R¹¹ is hydrogen orisopropyl. In a still further aspect, R¹¹ is hydrogen, propyl orisopropyl. In a yet further aspect, R¹¹ is hydrogen, isopropyl ortert-butyl.

In an aspect, R¹¹ is C1-C6 alkyl. In a further aspect, R¹¹ is methyl,ethyl, propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl,neopentyl, isopentyl, sec-pentyl, or tert-pentyl. In a still furtheraspect, R¹¹ is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, or isobutyl.

In a further aspect, R¹¹ is n-butyl, tert-butyl, sec-butyl, or isobutyl.In a still further aspect, R¹¹ is n-butyl. In a yet further aspect, R¹¹is tert-butyl. In an even further aspect, R¹¹ is sec-butyl. In a stillfurther aspect, R¹¹ is isobutyl.

In a further aspect, R¹¹ is methyl. In a still further aspect, R¹¹ isethyl. In a yet further aspect, R¹¹ is propyl. In an even furtheraspect, R¹¹ is isopropyl. In a still further aspect, R¹¹ is propyl orisopropyl. In a yet further aspect, R¹¹ is isopropyl or tert-butyl.

k. R¹² Groups

In an aspect, R¹² is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—OH,—(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar¹, or Cy¹.

In a further aspect, R¹² is hydrogen, cyano, halogen, C2-C6 alkyl, C1-C6monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6alkyl), —(C1-C6 alkyl)-(C═O)—(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—O(C1-C6alkyl), Ar¹, or Cy¹.

In a further aspect, R¹² is methyl, ethyl, propyl, isopropyl, n-butyl,tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, ortert-pentyl. In a still further aspect, R¹² is methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, sec-butyl, or isobutyl. In a yet furtheraspect, R¹² is methyl, ethyl, propyl, or isopropyl. In an even furtheraspect, R¹² is methyl or ethyl. In a still further aspect, R¹² ismethyl.

In a further aspect, R¹² is ethyl, propyl, isopropyl, n-butyl,tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, ortert-pentyl. In a still further aspect, R¹² is ethyl, propyl, isopropyl,n-butyl, tert-butyl, sec-butyl, or isobutyl. In a yet further aspect,R¹² is ethyl, propyl, or isopropyl. In an even further aspect, R¹² isethyl.

In a further aspect, R¹² is propyl, isopropyl, n-butyl, tert-butyl,sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, or tert-pentyl.In a still further aspect, R¹² is propyl, isopropyl, n-butyl,tert-butyl, sec-butyl, or isobutyl. In a yet further aspect, R¹² ispropyl or isopropyl. In an even further aspect, R¹² is propyl. In astill further aspect, R¹² is isopropyl.

1. Ar¹ Groups

In an aspect, Ar¹ is monocyclic aryl or monocyclic heteraryl substitutedwith 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino,C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3polyhaloalkyl.

m. Cy¹ Groups

In an aspect, Cy¹ is C3-C8 cycloalkyl or C2-C7 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy,cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, orC1-C3 polyhaloalkyl.

2. Example Compounds

In an aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In an aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In an aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In an aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In an aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In an aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In an aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

C. Pharmaceutical Compositions

In an aspect, the invention relates to pharmaceutical compositionscomprising the disclosed compounds and products of disclosed methods.That is, a pharmaceutical composition can be provided comprising aneffective amount of at least one disclosed compound, at least oneproduct of a disclosed method, or a pharmaceutically acceptable salt,thereof, and a pharmaceutically acceptable carrier. In an aspect, theinvention relates to pharmaceutical compositions comprising apharmaceutically acceptable carrier and an effective amount of at leastone disclosed compound; or a pharmaceutically acceptable salt, thereof.

In a further aspect, the effective amount is a therapeutically effectiveamount. In a still further aspect, the effective amount is aprophylactically effective amount. In a still further aspect, thepharmaceutical composition comprises a compound that is a product of adisclosed method of making.

In a further aspect, the pharmaceutical composition comprises atherapeutically effective amount of a compound having a structurerepresented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.

In a further aspect, the pharmaceutical composition comprises adisclosed compound. In a yet further aspect, the pharmaceuticalcomposition comprises a product of a disclosed method of making.

In a further aspect, the pharmaceutical composition comprises adisclosed compound that exhibits an IC₅₀ of less than or equal to about10 μM as determined in a time-resolved fluorescence resonance transfer(TR-FRET) hPXR competitive binding assay. In a still further aspect, thepharmaceutical composition comprises a disclosed compound that has anIC₅₀ of less than or equal to about 5.0 μM as determined in atime-resolved fluorescence resonance transfer (TR-FRET) hPXR competitivebinding assay. In a yet further aspect, the pharmaceutical compositioncomprises a disclosed compound that has an IC₅₀ of less than or equal toabout 2.5 μM as determined in a time-resolved fluorescence resonancetransfer (TR-FRET) hPXR competitive binding assay. In an even furtheraspect, the pharmaceutical composition comprises a disclosed compoundthat has an IC₅₀ of less than or equal to about 1.0 μM as determined ina time-resolved fluorescence resonance transfer (TR-FRET) hPXRcompetitive binding assay. In a still further aspect, the pharmaceuticalcomposition comprises a disclosed compound that has an IC₅₀ of less thanor equal to about 100 nM as determined in a time-resolved fluorescenceresonance transfer (TR-FRET) hPXR competitive binding assay. In a yetfurther aspect, the pharmaceutical composition comprises a disclosedcompound that has an IC₅₀ of less than or equal to about 1.0 nM asdetermined in a time-resolved fluorescence resonance transfer (TR-FRET)hPXR competitive binding assay.

In a further aspect, the pharmaceutical composition comprises adisclosed compound that exhibits an IC₅₀ of less than or equal to about10 μM as determined in an hPXR transactivation assay. In a still furtheraspect, the pharmaceutical composition comprises a disclosed compoundthat has an IC₅₀ of less than or equal to about 5.0 μM as determined inan hPXR transactivation assay. In a yet further aspect, thepharmaceutical composition comprises a disclosed compound that has anIC₅₀ of less than or equal to about 2.5 μM as determined in an hPXRtransactivation assay. In an even further aspect, the pharmaceuticalcomposition comprises a disclosed compound that has an IC₅₀ of less thanor equal to about 1.0 μM as determined in an hPXR transactivation assay.In a still further aspect, the pharmaceutical composition comprises adisclosed compound that has an IC₅₀ of less than or equal to about 100nM as determined in an hPXR transactivation assay. In a yet furtheraspect, the pharmaceutical composition comprises a disclosed compoundthat has an IC₅₀ of less than or equal to about 1.0 nM as determined inan hPXR transactivation assay.

In an aspect, the pharmaceutical composition is used to treat a mammal.In a further aspect, the mammal is a human. In a still further aspect,the mammal has been diagnosed with a need for treatment of an adversedrug reaction associated with PXR activity. In a yet further aspect, themammal has been diagnosed with a need for treatment of an adverse drugreaction associated with PXR activity prior to the administering step.In an even further aspect, the mammal has been identified to be in needof treatment of an adverse drug reaction. In a still further aspect, theadverse drug reaction is enhanced toxicity, increased metabolism, and/ordecreased efficacy. In a yet further aspect, the adverse drug reactionis associated with another therapeutic agent, and the pharmaceuticalcomposition is administered to treat the adverse drug reactionassociated with the other therapeutic agent. In an even further aspect,the adverse drug reaction is associated with another therapeutic agent,and the pharmaceutical composition is co-administered the othertherapeutic agent in order to treat the adverse drug reaction associatedwith the other therapeutic agent. In a further aspect, thepharmaceutical composition is used to treat an adverse drug reaction.

In a further aspect, the mammal has been diagnosed with a need fortreatment of an infectious disease. In a yet further aspect, the mammalhas been diagnosed with a need for treatment of an infectious diseaseprior to the administering step. In an even further aspect, the mammalhas been identified to be in need of treatment of an infectious disease.In a still further aspect, a therapeutic agent known to treat aninfectious disease is co-administered with the pharmaceuticalcomposition. In a yet further aspect, the therapeutic agent known totreat an infectious disease that is co-administered with thepharmaceutical composition is isoniazid, isoniazid in combination withrifampin, rifampicin, or flucloxacilline.

In a further aspect, the mammal has been diagnosed with a need fortreatment of an inflammatory disease. In a yet further aspect, themammal has been diagnosed with a need for treatment of an inflammatorydisease prior to the administering step. In an even further aspect, themammal has been identified to be in need of treatment of an inflammatorydisease. In a still further aspect, a therapeutic agent known to treatan inflammatory disease is co-administered with the pharmaceuticalcomposition. In a yet further aspect, the therapeutic agent known totreat an inflammatory disease that is co-administered with thepharmaceutical composition is acetaminophen.

In a further aspect, the mammal has been diagnosed with a need fortreatment of a seizure or convulsant disorder. In a yet further aspect,the mammal has been diagnosed with a need for treatment of a seizure orconvulsant disorder prior to the administering step. In an even furtheraspect, the mammal has been identified to be in need of treatment of aseizure or convulsant disorder. In a still further aspect, a therapeuticagent known to treat a seizure or convulsant disorder is co-administeredwith the pharmaceutical composition. In a yet further aspect, thetherapeutic agent known to treat a seizure or convulsant disorder thatis co-administered with the pharmaceutical composition is phenytoin.

In a further aspect, the mammal has been diagnosed with a need fortreatment of a disorder of uncontrolled cellular proliferation, such asa cancer. In a yet further aspect, the mammal has been diagnosed with aneed for treatment of a disorder of uncontrolled cellular proliferationprior to the administering step. In an even further aspect, the mammalhas been identified to be in need of treatment of a disorder ofuncontrolled cellular proliferation. In a still further aspect, atherapeutic agent known to treat a disorder of uncontrolled cellularproliferation is co-administered with the pharmaceutical composition. Ina yet further aspect, the therapeutic agent known to treat a disorder ofuncontrolled cellular proliferation that is co-administered with thepharmaceutical composition is paclitaxel, irinotecan, leucovorin,dasatinib, or erlotinib.

In various aspects, the pharmaceutical composition of the presentinvention comprises a pharmaceutically acceptable carrier; an effectiveamount of at least one disclosed compound; or a pharmaceuticallyacceptable salt thereof; and an anticancer agent. In a further aspect,the anticancer agent comprises a compound selected from paclitaxel,irinotecan, leucovorin, dasatinib, and erlotinib, or combinationsthereof. In a still further aspect, the anticancer agent comprises acompound selected from paclitaxel, docetaxel, vinblastine, vincristine,vinorelbine, camptothecin, topotecan, irinotecan, belotecan, gimatecan,inidimitecan, indotecan, Genz-644282, daunorubicin, epirubicin,etoposide, teniposide, mitoxantrone, ellipticinium, vasaroxin,dexrazoxane, mebarone,3-hydroxy-2-[(1R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-1,4-benzoquinone(HU-331), axitinib, crizotinib, dasatinib, erlotinib, gefitinib,imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib,sorafenib, sunitinib, vandetanib, vemurafenib, doxorubicin,mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin,idarubicin, plicamycin, mitomycin, pentostatin, valrubicin, gemcitabine,5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed,fludarabine, nelarabine, cladribine, clofarabine, cytarabine,decitabine, pralatrexate, floxuridine, methotrexate, methotrexatecoadministered with leucovorin, thioguanine, carboplatin, cisplatin,cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan,lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine,temozolomide, thiotepa, bendamustine, streptozocin, etopside,vincristine, ixabepilone, vinorelbine, vinblastine, teniposide,everolimus, siroliumus, temsirolimus, or combinations thereof.

In various aspects, the pharmaceutical composition of the presentinvention comprises a pharmaceutically acceptable carrier; an effectiveamount of at least one disclosed compound; or a pharmaceuticallyacceptable salt thereof; and an antibacterial agent. In a furtheraspect, the antibacterial agent comprises a compound selected fromisoniazid, isoniazid in combination with rifampin, rifampicin, andflucloxacillin, or combinations thereof.

In various aspects, the pharmaceutical composition of the presentinvention comprises a pharmaceutically acceptable carrier; an effectiveamount of at least one disclosed compound; or a pharmaceuticallyacceptable salt thereof; and a non-steroidal anti-inflammatory drug. Ina further aspect, the non-steroidal anti-inflammatory drug comprisesacetaminophen.

In various aspects, the pharmaceutical composition of the presentinvention comprises a pharmaceutically acceptable carrier; an effectiveamount of at least one disclosed compound; or a pharmaceuticallyacceptable salt thereof; and an anticonvulsant drug. In a furtheraspect, the anticonvulsant drug comprises acetaminophen phenytoin.

In certain aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases oracids. When the compound of the present invention is acidic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic bases, including inorganic bases and organic bases.Salts derived from such inorganic bases include aluminum, ammonium,calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium,manganese (-ic and -ous), potassium, sodium, zinc and the like salts.Particularly preferred are the ammonium, calcium, magnesium, potassiumand sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, as well as cyclic amines and substituted amines such asnaturally occurring and synthesized substituted amines. Otherpharmaceutically acceptable organic non-toxic bases from which salts canbe formed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

As used herein, the term “pharmaceutically acceptable non-toxic acids,”includes inorganic acids, organic acids, and salts prepared therefrom,for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

In practice, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier can take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, and/or pharmaceutically acceptable salt(s) thereof, can alsobe administered by controlled release means and/or delivery devices. Thecompositions can be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention can include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of the compounds of the invention. The compounds of theinvention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moreother therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In the treatment conditions which require modulation of PXR activity, anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day and can be administered in single ormultiple doses. Preferably, the dosage level will be about 0.1 to about250 mg/kg per day; more preferably 0.5 to 100 mg/kg per day. A suitabledosage level can be about 0.01 to 250 mg/kg per day, about 0.05 to 100mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range thedosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg/kg per day. Fororal administration, the compositions are preferably provided in theform of tablets containing 1.0 to 1000 milligrams of the activeingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150,200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of theactive ingredient for the symptomatic adjustment of the dosage of thepatient to be treated. The compound can be administered on a regimen of1 to 4 times per day, preferably once or twice per day. This dosingregimen can be adjusted to provide the optimal therapeutic response.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors. Such factorsinclude the age, body weight, general health, sex, and diet of thepatient. Other factors include the time and route of administration,rate of excretion, drug combination, and the type and severity of theparticular disease undergoing therapy.

The present invention is further directed to a method for themanufacture of a medicament for modulating PXR activity (e.g.,modulating adverse reactions or treating a disease of uncontrolledcellular proliferation) in mammals (e.g., humans) comprising combiningone or more disclosed compounds, products, or compositions with apharmaceutically acceptable carrier or diluent. Thus, in an aspect, theinvention relates to a method for manufacturing a medicament comprisingcombining at least one disclosed compound or at least one disclosedproduct with a pharmaceutically acceptable carrier or diluent.

The disclosed pharmaceutical compositions can further comprise othertherapeutically active compounds, which are usually applied in thetreatment of the above mentioned pathological conditions.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

D. Methods of Using the Compounds

Also provided is a method of use of a disclosed compound, composition,or medicament. In an aspect, the method of use is directed to thetreatment of an infectious disease. In a further aspect, the disclosedcompounds can be used as single agents or in combination with one ormore other drugs in the treatment, prevention, control, amelioration orreduction of risk of the aforementioned diseases, disorders andconditions for which the compound or the other drugs have utility, wherethe combination of drugs together are safer or more effective thaneither drug alone. The other drug(s) can be administered by a route andin an amount commonly used therefore, contemporaneously or sequentiallywith a disclosed compound. When a disclosed compound is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such drugs and the disclosedcompound is preferred. However, the combination therapy can also beadministered on overlapping schedules. It is also envisioned that thecombination of one or more active ingredients and a disclosed compoundcan be more efficacious than either as a single agent.

In an aspect, the disclosed compounds or products of a disclosed methodof making can be coadministered with an anticancer therapeutic agent. Ina further aspect, the anticancer therapeutic agent can be paclitaxel,irinotecan, leucovorin, dasatinib, or erlotinib, or combinationsthereof. In a still further aspect, anticancer therapeutic agent can bepaclitaxel, docetaxel, vinblastine, vincristine, vinorelbine,camptothecin, topotecan, irinotecan, belotecan, gimatecan, inidimitecan,indotecan, Genz-644282, daunorubicin, epirubicin, etoposide, teniposide,mitoxantrone, ellipticinium, vasaroxin, dexrazoxane, mebarone,3-hydroxy-2-[(1R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-1,4-benzoquinone(HU-331), axitinib, crizotinib, dasatinib, erlotinib, gefitinib,imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib,sorafenib, sunitinib, vandetanib, vemurafenib, doxorubicin,mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin,idarubicin, plicamycin, mitomycin, pentostatin, valrubicin, gemcitabine,5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed,fludarabine, nelarabine, cladribine, clofarabine, cytarabine,decitabine, pralatrexate, floxuridine, methotrexate, methotrexatecoadministered with leucovorin, thioguanine, carboplatin, cisplatin,cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan,lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine,temozolomide, thiotepa, bendamustine, streptozocin, etopside,vincristine, ixabepilone, vinorelbine, vinblastine, teniposide,everolimus, siroliumus, or temsirolimus, or combinations thereof.

In an aspect, the disclosed compounds or products of a disclosed methodof making can be coadministered with an anti-infectious or antibacterialtherapeutic agent. In a further aspect, the anti-infectious orantibacterial therapeutic agent can be isoniazid, isoniazid incombination with rifampin, rifampicin, or flucloxacillin, orcombinations thereof. In a still further aspect, the anti-infectious orantibacterial therapeutic agent can be amoxicillin, ampicillin,azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin,cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir,cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin,cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin,clarithromycin, clavulanic acid, clinafloxacin, clindamycin,clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin,daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline,erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol,flucloxacillin, fosfomycin, furazolidone, gatifloxacin, gentamicin,imipenem, isoniazid, kanamycin, linezolid, lomefloxacin, loracarbef,mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin,minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin,nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline,penicillin, piperacillin, platensimycin, polymixin B, quinupristin,retapamulin, rifabutin, rifampin, rifapentine, roxithromycin,sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole,sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin,tetracycline, tedolizid, thioacetazone, thioridazine, ticarcillin,tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim,troleandomycin, trovafloxacin, or vancomycin, or combinations thereof.

In an aspect, the disclosed compounds or products of a disclosed methodof making can be coadministered with a non-steroidal anti-inflammatorydrug. In a further aspect, the non-steroidal anti-inflammatory drugcomprises acetaminophen. In a still further aspect, the non-steroidalanti-inflammatory drug comprises diflusinal, ibuprofen, naproxen,ketoprofen, fenoprofen, flurbiprofen, fenbufen, benoxaprofen,tiaprofenic acid, indoprofen, suprofen, etodolac, zomepirac,indomethacin, alclofenac, sulindac, fenclofenac, diclofenac, tolmetin,mefanamic acid, phenylbutazone, oxyphenbuta, azapropazone, feprazone, orpiroxicam, or combinations thereof.

Provided are methods of using of a disclosed compound, pharmaceuticalcomposition, or medicament. In an aspect, the method of use is directedto the treatment of a disease or disorder.

In a further aspect, the disclosed compounds can be used as singleagents or in combination with one or more other drugs in the treatment,prevention, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions for which the compoundor the other drugs have utility, where the combination of drugs togetherare safer or more effective than either drug alone. The other drug(s)can be administered by a route and in an amount commonly used therefore,contemporaneously or sequentially with a disclosed compound. When adisclosed compound is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchdrugs and the disclosed compound is preferred. However, the combinationtherapy can also be administered on overlapping schedules. It is alsoenvisioned that the combination of one or more active ingredients and adisclosed compound can be more efficacious than either as a singleagent.

The pharmaceutical compositions and methods of the present invention canfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

1. Treatment Methods

The compounds disclosed herein are useful for treating, preventing,ameliorating, controlling or reducing the risk of a variety of adversereactions associated with therapeutic agents normally given to treatcancer, infectious disease, seizure or convulsant disorders, andinflammatory diseases. For example, a treatment can includeadministration of the disclosed compounds to modulate, e.g., inhibitionactivity of PXR. The activity of PXR can be upregulated byadministration of a number of therapeutic agents as discussed herein.Thus, provided is a method of treating or preventing a disorder in asubject comprising the step of administering to the subject at least onedisclosed compound; at least one disclosed pharmaceutical composition;and/or at least one disclosed product in a dosage and amount effectiveto treat an adverse reaction in the subject.

Alternatively, the disclosed compounds can be co-administered with atherapeutic agent that is being administered to treat a disease such ascancer, an infectious disease, an inflammatory disorder, or a seizure orconvulsant disorder. It should be understood that “co-administration”can refer to simultaneous administration of the disclosed compounds withanother therapeutic agent. Simultaneous administration is understood tocomprise administration of two separate dosage forms, such as one dosageform for the disclosed compound and one dosage form for the othertherapeutic agent. Alternatively, simultaneous administration cancomprise co-formulation or co-packaging of the disclosed compound andthe other therapeutic agent. Further, it should be understood that“co-administration” can refer sequential administration of the disclosedcompound and the other therapeutic agent. Sequential administrationcomprises a first administration of the disclosed compound followed by asecond administration of the other therapeutic agent, or alternatively,a first administration of the other therapeutic agent followed byadministration of the disclosed compound. The time interval between thefirst and second administration can be as needed to obtain the mostefficacious treatment outcomes, e.g., the time interval between thefirst and second administration can be about one minute, five minutes,ten minutes, fifteen minutes, 20 minutes, 30 minutes, 45 minutes, 60minutes, 90 minutes, two hours, three hours, four hours, five hours, sixhours, eight hours, ten hours, fifteen hours, 20 hours, 24 hours, twodays, three days, four days, five days, six days, seven days, two weeks,three week, four weeks, two months, or three months.

In an aspect, the disclosed compounds can be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichdisclosed compounds or the other drugs can have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) can be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and a disclosed compound is preferred. However, thecombination therapy can also include therapies in which a disclosedcompound and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the disclosedcompounds and the other active ingredients can be used in lower dosesthan when each is used singly.

Accordingly, the pharmaceutical compositions include those that containone or more other active ingredients, in addition to a compound of thepresent invention.

The above combinations include combinations of a disclosed compound notonly with one other active compound, but also with two or more otheractive compounds. Likewise, disclosed compounds can be used incombination with other drugs that are used in the prevention, treatment,control, amelioration, or reduction of risk of the diseases orconditions for which disclosed compounds are useful. Such other drugscan be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to a disclosedcompound is preferred. Accordingly, the pharmaceutical compositionsinclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of a disclosed compound to the second active ingredientcan be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the present invention is combined withanother agent, the weight ratio of a disclosed compound to the otheragent will generally range from about 1000:1 to about 1;1000, preferablyabout 200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

In such combinations a disclosed compound and other active agents can beadministered separately or in conjunction. In addition, theadministration of one element can be prior to, concurrent to, orsubsequent to the administration of other agent(s).

Accordingly, the disclosed compounds can be used alone or in combinationwith other agents which are known to be beneficial in the subjectindications or other drugs that affect receptors or enzymes that eitherincrease the efficacy, safety, convenience, or reduce unwanted sideeffects or toxicity of the disclosed compounds. The subject compound andthe other agent can be coadministered, either in concomitant therapy orin a fixed combination.

Also provided are methods for the treatment of one or more disordersassociated with dysregulation of PXR in a subject, comprising the stepof administering to the subject at least one disclosed compound, atleast one disclosed compound with at least one other disclosedtherapeutic agent, at least one disclosed pharmaceutical composition,and/or at least one disclosed medicament in a dosage and treatmentfrequency effective to treat the disorder in the subject.

Also provided are methods for the treatment in a mammal comprising thestep of administering to the mammal at least one disclosed compound, atleast one disclosed compound with at least one other disclosedtherapeutic agent, at least one disclosed pharmaceutical composition, orat least one disclosed medicament.

In the treatment of a disease or disorder or pathological condition, asdisclosed herein, an appropriate dosage level will generally be about0.01 to 500 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level can be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15. 20,25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and1000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated. The compounds can beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day. This dosage regimen can be adjusted to provide theoptimal therapeutic response. It will be understood, however, that thespecific dose level and frequency of dosage for any particular patientcan be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

Thus, In an aspect, the invention relates to a method for inhibiting PXRactivity in at least one cell, e.g. a mammalian cell, comprising thestep of contacting the at least one cell with at least one disclosedcompound, at least one product of a disclosed method, and/or at leastone disclosed pharmaceutical composition in an amount effective toinhibit PXR activity in the at least one cell. In a further aspect, thecell is mammalian cell, e.g., a human cell. In a further aspect, thecell has been isolated from a subject prior to the contacting step. In afurther aspect, contacting is via administration to a subject.

a. Methods for Modulating an Adverse Drug Reaction in a Mammal

In an aspect, the invention relates to a method for modulating anadverse drug reaction in a mammal comprising the step of administeringto the mammal a therapeutically effective amount of at least onedisclosed compound, or a pharmaceutically acceptable salt thereof; atleast one disclosed pharmaceutical composition; or at least onedisclosed medicament; or a compound having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

In a further aspect, the compound administered is a product of adisclosed method of making. In a still further aspect, an effectiveamount is a therapeutically effective amount. In a yet further aspect,an effective amount is a prophylactically effective amount.

In a further aspect, the mammal is a human. In a still further aspect,the mammal has been diagnosed with a need for modulating an adverse drugreaction prior to the administering step. In an even further aspect, themethod further comprises the step of identifying a mammal in need ofmodulating an adverse drug reaction. In a still further aspect,modulating an adverse drug reaction is associated with the mammalreceiving treatment for a disorder of uncontrolled cellularproliferation. In a yet further aspect, modulating an adverse drugreaction is associated with the mammal receiving treatment for adisorder of uncontrolled cellular proliferation, and the disorder ofuncontrolled cellular proliferation is a cancer.

In various aspects, the compound administered exhibits an IC₅₀ of lessthan about μM. In a further aspect, the compound administered exhibitsan IC₅₀ of less than about 10 μM. In a still further aspect the compoundadministered exhibits an IC₅₀ of less than about 5.0 μM. In a yetfurther aspect, the compound administered exhibits an IC₅₀ of less thanabout 2.5 μM. In an even further aspect, the compound administeredexhibits an IC₅₀ of less than about 1.0 μM. In a still further aspect,the compound administered exhibits an IC₅₀ of less than about 750 nM. Ina yet further aspect, the compound administered exhibits an IC₅₀ of lessthan about 500 nM. In an even further aspect, the compound administeredexhibits an IC₅₀ of less than about 250 nM. In a still further aspect,the compound administered exhibits an IC₅₀ of less than about 100 nM. Ina yet further aspect, the compound administered exhibits an IC₅₀ of lessthan about 50 nM. In an even further aspect, the compound administeredexhibits an IC₅₀ of less than about 25 nM. In a still further aspect,the compound administered exhibits an IC₅₀ of less than about 10 nM.

It is understood, that in various aspects, the IC₅₀ of the compoundadministered can be determined by methods disclosed herein, e.g., thetime-resolved fluorescence resonance transfer (TR-FRET) hPXR competitivebinding assay or the hPXR transactivation assay. That is, in aspects,the IC₅₀ should be understood to be the IC₅₀ as determined in thetime-resolved fluorescence resonance transfer (TR-FRET) hPXR competitivebinding assay described herein. Alternatively, in aspects, the IC₅₀should be understood to be the IC₅₀ as determined in the hPXRtransactivation assay.

In various aspects, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent. In a further aspect, the administration isco-administration of the at least one disclosed compound or thepharmaceutical composition with another therapeutic agent. In a stillfurther aspect, the administration is sequential administration of theat least one disclosed compound or the pharmaceutical composition withanother therapeutic agent.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, and the other therapeutic agent is an anticanceragent. In a yet further aspect, the anticancer agent administered withthe at least one disclosed compound or the disclosed pharmaceuticalcomposition is paclitaxel, irinotecan, leucovorin, dasatinib, orerlotinib.

In a further aspect, the anticancer agent administered with the at leastone disclosed compound or the disclosed pharmaceutical composition is atopoisomerase inhibitor. In a still further aspect, the topoisomeraseinhibitor is camptothecin, topotecan, irinotecan, belotecan, gimatecan,inidimitecan, indotecan, Genz-644282, daunorubicin, epirubicin,etoposide, teniposide, mitoxantrone, ellipticinium, vasaroxin,dexrazoxane, mebarone, or3-hydroxy-2-[(1R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-1,4-benzoquinone(HU-331). In a yet further aspect, the topoisomerase inhibitor isirinotecan.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is an anticancer agent,and the anticancer agent is a tyrosine kinase inhibitor. In a stillfurther aspect, the tyrosine kinase inhibitor is axitinib, crizotinib,dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib,pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib,or vemurafenib. In a yet further aspect, the tyrosine kinase inhibitoris dasatinib or erlotinib.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is an anticancer agent,and the anticancer agent is a mitotic inhibitor. In a still furtheraspect, the mitotic inhibitor is paclitaxel, docetaxel, vinblastine,vincristine, or vinorelbine. In a yet further aspect, the mitoticinhibitor is paclitaxel or docetaxel. In an even further aspect, themitotic inhibitor is paclitaxel.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is an anticancer agent,and the anticancer agent is a chemotherapeutic agent. In a still furtheraspect, the chemotherapeutic agent is an alkylating-like agent, anantimetabolite agent, an antineoplastic antibiotic agent, a mitoticinhibitor agent, an mTor inhibitor agent, or other chemotherapeuticagent.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is an anticancer agent,and the anticancer agent is an antineoplastic agent selected from one ormore of doxorubicin, mitoxantrone, bleomycin, daunorubicin,dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin,pentostatin, and valrubicin, or a pharmaceutically acceptable saltthereof.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is an anticancer agent,and the anticancer agent is an antimetabolite agent selected from one ormore of the group consisting of gemcitabine, 5-fluorouracil,capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine,nelarabine, cladribine, clofarabine, cytarabine, decitabine,pralatrexate, floxuridine, methotrexate, methotrexate coadministeredwith leucovorin, and thioguanine, or a pharmaceutically acceptable saltthereof.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is an anticancer agent,and the anticancer agent is an alkylating-like agent is selected fromone or more of the group consisting of carboplatin, cisplatin,cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan,lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine,temozolomide, thiotepa, bendamustine, and streptozocin, or apharmaceutically acceptable salt thereof.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is an anticancer agent,and the anticancer agent is a mitotic inhibitor agent is selected fromone or more of the group consisting of etopside, vincristine,ixabepilone, vinorelbine, vinblastine, and teniposide, or apharmaceutically acceptable salt thereof.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is an anticancer agent,and the anticancer agent is a mTor inhibitor agent is selected from oneor more of the group consisting of everolimus, siroliumus, andtemsirolimus, or a pharmaceutically acceptable salt thereof.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is an antibacterialagent. In a still further aspect, the antibacterial agent is isoniazid,isoniazid in combination with rifampin, rifampicin, or flucloxacillin.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is a non-steroidalanti-inflammatory drug. In a still further aspect, the non-steroidalanti-inflammatory drug is acetominophen.

In a further aspect, the method for modulating an adverse drug reactionin a mammal further comprises administration of the at least onedisclosed compound or the pharmaceutical composition with anothertherapeutic agent, the other therapeutic agent is an anticonvulsantdrug. In a still further aspect, the anticonvulsant drug is phenytoin.

b. Methods for Treatment of a Disorder of Uncontrolled CellularProliferation

In an aspect, the invention relates to a method for treatment of adisorder of uncontrolled cellular proliferation in a mammal comprisingthe step of administering to the mammal a therapeutically effectiveamount of at least one disclosed compound, or a pharmaceuticallyacceptable salt thereof; at least one disclosed pharmaceuticalcomposition; or at least one disclosed medicament; or a compound havinga structure represented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

In a further aspect, the compound administered is a product of adisclosed method of making. In a still further aspect, an effectiveamount is a therapeutically effective amount. In a yet further aspect,an effective amount is a prophylactically effective amount.

In a further aspect, the mammal is a human. In a still further aspect,the mammal has been diagnosed with a need for treatment of the disorderof uncontrolled cellular proliferation prior to the administering step.In a yet further aspect, the method for treating a disorder of cellularproliferation further comprises the step of identifying a mammal in needof treatment of the disorder of uncontrolled cellular proliferation.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation is a method for treating cancer. In a stillfurther aspect, the cancer is selected from breast cancer, renal cancer,gastric cancer, and colorectal cancer. In a yet further aspect, thecancer is selected from lymphoma, cancers of the brain, genitourinarytract cancer, lymphatic system cancer, stomach cancer, larynx cancer,lung, pancreatic cancer, breast cancer, and malignant melanoma.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition with ananticancer agent. In a further aspect, the administration of the atleast one disclosed compound or the pharmaceutical composition with ananticancer agent co-administration of the at least one disclosedcompound or the pharmaceutical composition with another therapeuticagent. In a still further aspect, the administration of the at least onedisclosed compound or the pharmaceutical composition with an anticanceragent is sequential administration of the at least one disclosedcompound or the pharmaceutical composition with another therapeuticagent.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition withpaclitaxel, irinotecan, leucovorin, dasatinib, or erlotinib.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition a topoisomeraseinhibitor. In a still further aspect, the topoisomerase inhibitor iscamptothecin, topotecan, irinotecan, belotecan, gimatecan, inidimitecan,indotecan, Genz-644282, daunorubicin, epirubicin, etoposide, teniposide,mitoxantrone, ellipticinium, vasaroxin, dexrazoxane, mebarone, or3-hydroxy-2-[(1R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-1,4-benzoquinone(HU-331). In a yet further aspect, the topoisomerase inhibitor isirinotecan.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition a tyrosinekinase inhibitor. In a still further aspect, the tyrosine kinaseinhibitor is axitinib, crizotinib, dasatinib, erlotinib, gefitinib,imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib,sorafenib, sunitinib, vandetanib, or vemurafenib. In a yet furtheraspect, the tyrosine kinase inhibitor is dasatinib or erlotinib.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition a mitoticinhibitor. In a still further aspect, the mitotic inhibitor ispaclitaxel, docetaxel, vinblastine, vincristine, or vinorelbine. In ayet further aspect, the mitotic inhibitor is paclitaxel or docetaxel. Inan even further aspect, the mitotic inhibitor is paclitaxel.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition achemotherapeutic agent. In a still further aspect, the chemotherapeuticagent is an alkylating-like agent, an antimetabolite agent, anantineoplastic antibiotic agent, a mitotic inhibitor agent, an mTorinhibitor agent, or other chemotherapeutic agent.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition anantineoplastic agent selected from one or more of doxorubicin,mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin,idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or apharmaceutically acceptable salt thereof.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition anantimetabolite agent selected from one or more of the group consistingof gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea,mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine,clofarabine, cytarabine, decitabine, pralatrexate, floxuridine,methotrexate, methotrexate coadministered with leucovorin, andthioguanine, or a pharmaceutically acceptable salt thereof.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition analkylating-like agent selected from one or more of the group consistingof carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan,carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide,mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin,or a pharmaceutically acceptable salt thereof.

In a further aspect, the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition a mitoticinhibitor agent selected from one or more of the group consisting ofetopside, vincristine, ixabepilone, vinorelbine, vinblastine, andteniposide, or a pharmaceutically acceptable salt thereof.

In a further aspect the method for treating a disorder of uncontrolledcellular proliferation further comprises administration of the at leastone disclosed compound or the pharmaceutical composition a mTorinhibitor agent selected from one or more of the group consisting ofeverolimus, siroliumus, and temsirolimus, or a pharmaceuticallyacceptable salt thereof.

c. Method for Modulating Pregnane X Receptor Activity in a Mammal

In an aspect, the invention relates to a method for modulating pregnaneX receptor activity in a mammal comprising the step of administering tothe mammal a therapeutically effective amount of at least one disclosedcompound, or a pharmaceutically acceptable salt thereof; at least onedisclosed pharmaceutical composition; or at least one disclosedmedicament; or a compound having a structure represented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

In a further aspect, the compound administered in the method formodulating pregnane X receptor activity in a mammal is a product of adisclosed method of making. In a still further aspect, an effectiveamount is a therapeutically effective amount. In a yet further aspect,an effective amount is a prophylactically effective amount.

In a further aspect, the method for modulating pregnane X receptoractivity in a mammal is a method for modulating pregnane X receptoractivity in a human.

In a further aspect, the mammal has been diagnosed with a need formodulating pregnane X receptor activity prior to the administering step.In a yet further aspect, the method further comprises the step ofidentifying a mammal in need of modulating pregnane X receptor activity.

d. Modulating Pregnane X Receptor Activity in at Least One Cell

In an aspect, the invention relates to a method for modulating pregnaneX receptor activity in at least one cell, comprising the step ofcontacting the at least one cell with an effective amount of at leastone disclosed compound, or a pharmaceutically acceptable salt thereof;at least one disclosed pharmaceutical composition; or at least onedisclosed medicament; or a compound having a structure represented by aformula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.

In a further aspect, the cell contacted is a mammalian cell. In a stillfurther aspect, the cell contacted is a human cell. In a yet furtheraspect, the cell contacted has been isolated from a mammal prior to thecontacting step. In an even further aspect, the contacting of the cellis ex vivo. In a still further aspect, the contacting of the cell is invitro.

In a further aspect, the contacting of the cell is via administration toa mammal. In a still further aspect, the mammal has been diagnosed witha need for modulating pregnane X receptor activity prior to theadministering step. In a yet further aspect, the mammal has beendiagnosed with a need for treatment of a disorder related to pregnane Xreceptor activity prior to the administering step.

2. Manufacture of a Medicament

In an aspect, the invention relates to a medicament comprising one ormore disclosed compounds, a product of a disclosed method of making, adisclosed pharmaceutical composition, or a compound having a structurerepresented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof. In a further aspect, themedicament is manufactured using a product of a disclosed method ofmaking. In a still further aspect, the medicament is manufactured usinga disclosed compound.

In various aspect, the invention relates methods for the manufacture ofa medicament for modulating pregnane X receptor activity (e.g.,treatment of an adverse drug reaction to a drug used to treat a diseasesuch as a cancer, an infectious disease, an inflammatory disease, or aseizure or convulsant disorder) in mammals (e.g., humans) comprisingcombining one or more disclosed compounds, products, or compositions ora pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, with a pharmaceutically acceptable carrier. It is understoodthat the disclosed methods can be performed with the disclosedcompounds, products, and pharmaceutical compositions. It is alsounderstood that the disclosed methods can be employed in connection withthe disclosed methods of using.

In a further aspect, the invention pertains to use of a disclosedcompound or a disclosed product in the manufacture of a medicament formodulating an adverse drug reaction in a mammal.

In a further aspect, the invention pertains to use of a disclosedcompound or a disclosed product in the manufacture of a medicament fortreatment of a disorder of uncontrolled cellular proliferation in amammal.

In a further aspect, the invention pertains to use of a disclosedcompound or a disclosed product in the manufacture of a medicament formodulating pregnane X receptor activity in a mammal comprising the stepof administering to the mammal.

In a further aspect, the invention pertains to use of a disclosedcompound or a disclosed product in the manufacture of a medicament formodulating pregnane X receptor activity in at least one cell, comprisingthe step of contacting the cell.

3. Uses of Compounds

Also provided are the uses of the disclosed compounds and products. Inone aspect, the invention relates to use of at least one disclosedcompound, at least one product of a disclosed method of making, adisclosed pharmaceutical composition, a disclosed medicament, or acompound having a structure represented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof. In a further aspect, thecompound used is a product of a disclosed method of making. In a furtheraspect, the compound used is a disclosed compound.

In various aspects, the compound used exhibits an IC₅₀ of less thanabout 15 μM. In a further aspect, the compound used exhibits an IC₅₀ ofless than about 10 μM. In a still further aspect the compound usedexhibits an IC₅₀ of less than about 5.0 μM. In a yet further aspect, thecompound used exhibits an IC₅₀ of less than about 2.5 μM. In an evenfurther aspect, the compound used exhibits an IC₅₀ of less than about1.0 μM. In a still further aspect, the compound used exhibits an IC₅₀ ofless than about 750 nM. In a yet further aspect, the compound usedexhibits an IC₅₀ of less than about 500 nM. In an even further aspect,the compound used exhibits an IC₅₀ of less than about 250 nM. In a stillfurther aspect, the compound used exhibits an IC₅₀ of less than about100 nM. In a yet further aspect, the compound used exhibits an IC₅₀ ofless than about 50 nM. In an even further aspect, the compound usedexhibits an IC₅₀ of less than about 25 nM. In a still further aspect,the compound used exhibits an IC₅₀ of less than about 10 nM.

It is understood, that in various aspects, the IC₅₀ of the compound usedcan be determined by methods disclosed herein, e.g., the time-resolvedfluorescence resonance transfer (TR-FRET) hPXR competitive binding assayor the hPXR transactivation assay. That is, in aspects, the IC₅₀ shouldbe understood to be the IC₅₀ as determined in the time-resolvedfluorescence resonance transfer (TR-FRET) hPXR competitive binding assaydescribed herein. Alternatively, in aspects, the IC₅₀ should beunderstood to be the IC₅₀ as determined in the hPXR transactivationassay.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method of making, ora pharmaceutically acceptable salt thereof, for use as a medicament.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method of making, ora pharmaceutically acceptable salt thereof, wherein a pharmaceuticallyacceptable carrier is intimately mixed with a therapeutically effectiveamount of the compound or the product of a disclosed method of making.

4. Kits

In an aspect, disclosed are kits comprising at least one disclosedcompound, at least one product of a disclosed method of making, adisclosed pharmaceutical composition, a disclosed medicament, or acompound having a structure represented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)—(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R⁵is hydrogen, halogen, hydroxy, C1-C3 alkyl; wherein R⁶ is hydrogen,halogen, hydroxy, C1-C3 alkyl; wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof; and one or more of: (a) atleast one agent known to increase pregnane X receptor activity; (b) atleast one agent known to decrease pregnane X receptor activity; (c) atleast one agent known to treat a disorder of uncontrolled cellularproliferation; (d) at least one agent known to treat an infectiousdisease; (e) at least one agent known to be a non-steroidalanti-inflammatory drug; (f) at least one agent known to be ananti-convulsant agent; or (g) instructions for treating a disorderassociated with pregnane X receptor dysfunction.

In various aspects, the disclosed compounds, products of a disclosedmethod of making, a disclosed medicament, the disclosed othertherapeutic agents, and the disclosed pharmaceutical compositionsdescribed herein can be provided in a kit as described herein. The kitcan also include combinations of the disclosed compounds, products of adisclosed method of making, a disclosed medicament, the disclosed othertherapeutic agents, and the disclosed pharmaceutical compositionsdescribed herein.

In various aspects, the instructions or informational material providedin the kit can be descriptive, instructional, marketing or othermaterial that relates to the methods described herein and/or to the useof the agents for the methods described herein. For example, theinformational material may relate to the use of the agents herein totreat a subject who has, or who is at risk for developing, an adversereaction. The kits can also include paraphernalia for administering theagents of this invention to a cell (in culture or in vivo) and/or foradministering a cell to a patient.

In various aspects, the instructions or informational material providedin the kit can include instructions for administering the pharmaceuticalcomposition and/or cell(s) in a suitable manner to treat a human, e.g.,in a suitable dose, dosage form, or mode of administration (e.g., adose, dosage form, or mode of administration described herein). In afurther aspect, the informational material can include instructions toadminister the pharmaceutical composition to a suitable subject, e.g., ahuman having, or at risk for developing, an adverse reaction.

In various aspects, the composition of the kit can include otheringredients, such as a solvent or buffer, a stabilizer, a preservative,a fragrance or other cosmetic ingredient. In such aspects, the kit caninclude instructions for admixing the agent and the other ingredients,or for using one or more compounds together with the other ingredients.

In a further aspect, the at least one compound and the therapeutic agentare co-formulated. In a still further aspect, the at least one compoundand the therapeutic agent are co-packaged.

In a further aspect, the kit can further comprise a plurality of dosageforms, the plurality comprising one or more doses; wherein each dosecomprises an effective amount of the disclosed compound or product of adisclosed method of making and the at least one agent. In a stillfurther aspect, the effective amount is a therapeutically effectiveamount. In yet a further aspect, the effective amount is aprophylactically effective amount. In an even further aspect, each doseof the disclosed compound or product of a disclosed method of making andthe therapeutic agent are co-packaged. In a still further aspect, eachdose of the disclosed compound or product of a disclosed method ofmaking and the therapeutic agent are co-formulated.

In a further aspect, the dosage forms are formulated for topicaladministration. In a still further aspect, the dosage forms areformulated for oral administration. In a yet further aspect, the dosageforms are formulated for administration via an injection, e.g.,intraperitoneal, intravenous, or intramuscular injection.

In a further aspect, the at least one agent in the kit is an anticanceragent. In a still further aspect, the at least one agent in the kit isan anticancer agent, and the anticancer agent is paclitaxel, irinotecan,leucovorin, dasatinib, or erlotinib.

In a further aspect, the at least one agent in the kit is an anticanceragent, and the anticancer agent is a topoisomerase inhibitor. In a stillfurther aspect, the topoisomerase inhibitor is camptothecin, topotecan,irinotecan, belotecan, gimatecan, inidimitecan, indotecan, Genz-644282,daunorubicin, epirubicin, etoposide, teniposide, mitoxantrone,ellipticinium, vasaroxin, dexrazoxane, mebarone, or3-hydroxy-2-[(1R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-1,4-benzoquinone(HU-331). In a yet further aspect, the topoisomerase inhibitor isirinotecan.

In a further aspect, the at least one agent in the kit is an anticanceragent, and the anticancer agent is a tyrosine kinase inhibitor. In astill further aspect, the tyrosine kinase inhibitor is axitinib,crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib,nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib,vandetanib, or vemurafenib. In a yet further aspect, the tyrosine kinaseinhibitor is dasatinib or erlotinib.

In a further aspect, the at least one agent in the kit is an anticanceragent, and the anticancer agent is a mitotic inhibitor. In a stillfurther aspect, the mitotic inhibitor is paclitaxel, docetaxel,vinblastine, vincristine, or vinorelbine. In a yet further aspect, themitotic inhibitor is paclitaxel or docetaxel. In an even further aspect,the mitotic inhibitor is paclitaxel.

In a further aspect, the at least one agent in the kit is an anticanceragent, and the anticancer agent is a chemotherapeutic agent. In a stillfurther aspect, the chemotherapeutic agent is an alkylating-like agent,an antimetabolite agent, an antineoplastic antibiotic agent, a mitoticinhibitor agent, an mTor inhibitor agent, or other chemotherapeuticagent.

In a further aspect, the at least one agent in the kit is an anticanceragent, and the anticancer agent is an antineoplastic antibiotic agentselected from one or more of the group consisting of doxorubicin,mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin,idarubicin, plicamycin, mitomycin, pentostatin, or valrubicin, or apharmaceutically acceptable salt thereof.

In a further aspect, the at least one agent in the kit is an anticanceragent, and the anticancer agent is an antimetabolite agent selected fromone or more of the group consisting of gemcitabine, 5-fluorouracil,capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine,nelarabine, cladribine, clofarabine, cytarabine, decitabine,pralatrexate, floxuridine, methotrexate, methotrexate coadministeredwith leucovorin, and thioguanine, or a pharmaceutically acceptable saltthereof.

In a further aspect, the at least one agent in the kit is an anticanceragent, and the anticancer agent is an alkylating-like agent selectedfrom one or more of the group consisting of carboplatin, cisplatin,cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan,lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine,temozolomide, thiotepa, bendamustine, and streptozocin, or apharmaceutically acceptable salt thereof.

In a further aspect, the at least one agent in the kit is an anticanceragent, and the anticancer agent is a mitotic inhibitor agent selectedfrom one or more of the group consisting of etopside, vincristine,ixabepilone, vinorelbine, vinblastine, and teniposide, or apharmaceutically acceptable salt thereof.

In a further aspect, the at least one agent in the kit is an anticanceragent, and the anticancer agent is an mTor inhibitor agent selected fromone or more of the group consisting of everolimus, siroliumus, andtemsirolimus, or a pharmaceutically acceptable salt thereof.

In a further aspect, the at least one agent in the kit is anantibacterial agent. In a still further aspect, the antibacterial agentis isoniazid, isoniazid in combination with rifampin, rifampicin, orflucloxacillin.

In a further aspect, the at least one agent in the kit is anon-steroidal anti-inflammatory drug. In a still further aspect, thenon-steroidal anti-inflammatory drug is acetominophen.

In a further aspect, the at least one agent in the kit is ananticonvulsant drug. In a still further aspect, the anticonvulsant drugis phenytoin.

5. Non-Medical Uses

Also provided are the uses of the disclosed compositions and products aspharmacological tools in the development and standardization of in vitroand in vivo test systems for the evaluation of the effect of PXR bindingrelated activity in laboratory animals such as cats, dogs, rabbits,monkeys, rats and mice, as part of the search for new therapeutic agentsof preventing undesired drug-drug interactions. In a further aspect, theinvention relates to the use of a disclosed compound or a disclosedproduct as pharmacological tools in the development and standardizationof in vitro and in vivo test systems for the evaluation of the effect ofPXR binding related activity in laboratory animals such as cats, dogs,rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents of preventing ligand binding interactions with PXR.

E. Examples

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

The Examples are provided herein to illustrate the invention, and shouldnot be construed as limiting the invention in any way. Examples areprovided herein to illustrate the invention and should not be construedas limiting the invention in any way.

1. General Chemistry Experimentals

Organic reagents were purchased from commercial suppliers unlessotherwise noted and were used without further purification. All solventswere analytical- or reagent-grade. All reactions were carried out inflame-dried glassware under argon or nitrogen. Flash columnchromatography was performed by using Sigma-Aldrich silica gel 60(200-400 mesh) and carried out under moderate pressure, with columns ofan appropriate size packed and eluted with appropriate eluents. Allreactions were monitored by performing thin-layer chromatography (TLC)on precoated plates (silica gel HLF). TLC spots were visualized eitherby exposure to iodine vapor or by irradiation with UV light. Organicsolvents were removed under vacuum by a rotary evaporator. Thereactions, purities, or identities of final compounds were monitored ordetermined by performing TLC or using a Waters Acquity UPLC MS systemwith a C18 column in a 2-min gradient (H₂O+0.1% formicacid→Acetonitrile+0.1% formic acid) and detectors of PDA (215-400 nm),ELSD, and Acquity SQD ESI Positive MS. Preparative TLC separation wasperformed by using self-casted preparative TLC plates with Sigma-Aldrichsilica gel 60 (200-400 mesh) on 20-cm×20-cm glass plates. Thepurifications of reaction products were performed by using a Dionex APS3000 dual purification/analytical LC/PDA/MS system with a C18 column ina 15-min gradient (H₂O with 0.05% NH3.H2O→Acetonitrile) and ESI PositiveMS. High-resolution mass spectra were determined by using a WatersAcquity UPLC system with a C18 column (H₂O+0.1% formicacid→acetonitrile+0.1% formic acid gradient over 2.5 min) under XevoG2Q-TOF ESI in positive, resolution mode. Compounds were internallynormalized to leucine-enkephalin lock solution, with a calculated errorof <3 ppm. All ¹H NMR spectra were recorded on a Bruker ULTRASHIELD 400plus NMR spectrometer and all ¹³C NMR spectra were recorded on a BrukerAscend 126 MHz Fourier transform (FT) NMR spectrometer at roomtemperature. The chemical shift values are expressed in parts permillion (ppm) relative to tetramethylsilane as the internal standard.Coupling constants (J) are reported in hertz (Hz).

Abbreviations: PXR, pregnane X receptor; rt, room temperature; THF,tetrahydrofuran; DMF, dimethylformamide; Pd(dppf)Cl₂,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); NFSI,N-fluorodibenzenesulfonimide; HATU,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate; TEA, triethylolamine; DCM, dichloromethane;DPPA, diphenylphosphoryl azide; AcOH, acetic acid; SEMCl,2-chloromethoxyethyl)trimethylsilane; NBS, N-bromosuccinimide; AIBN,azobisisobutyronitrile; TBAF, tetra-n-butylammonium fluoride.

2. Chemistry Experimentals

a. General Synthesis of Compounds LC-8, LC-10, LC-19, LC-20, and LC-29

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(4-fluoro-2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole(LC-8) (1) Synthesis of 90a

NaNO₂ (248 mg, 3.6 mmol) in water (1 mL) was added to a solution of 89a(4-fluoro-2,5-dimethoxyaniline, 513 mg, 3 mmol) in conc. HCl (10 mL) at0° C. and the reaction mixture was then stirred for 15 minutes at 0° C.A solution of NaN₃ (234 mg, 3.6 mmol) in water (1 mL) was addeddropwise. The solution was then stirred for 2 hours at ambienttemperature. The reaction mixture was extracted with hexane. The hexanelayer was washed with water, dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor to give product 90a (332 mg, 56% yield).

(2) Synthesis of LC-8

MeONa (108 mg, 2 mmol) and1-((4-(tert-butyl)phenyl)sulfonyl)propan-2-one (254 mg, 1 mmol) wereadded to a solution of compound 90a (197 mg, 1 mmol) in MeOH. Themixture was stirred at 60° C. overnight. The reaction was then pouredinto water and extracted with EtOAc. The EtOAc layer was washed withwater, dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor.The residue was purified by preparative HPLC to give product LC-8 (98mg, 23% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) δ 8.03 (d, 2H, J=8.4Hz), 7.56 (d, 2H, J=8.4 Hz), 6.94 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=12.4Hz), 3.82 (s, 3H), 3.73 (s, 3H), 2.43 (s, 3H), 1.32 (s, 9H). ESI-MS: m/z434 (M+H)⁺.

ii. Preparation of1-(4-bromo-2,5-dimethoxyphenyl)-4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazole(LC-10) (1) Synthesis of 90b

NaNO₂ (20 g, 0.29 mol) in water (100 mL) was added to a solution of 89b(4-bromo-2,5-dimethoxyaniline, 50 g, 0.22 mol) in conc. HCl (200 mL) at0° C. and the reaction mixture was then stirred for 15 minutes at 0° C.A solution of NaN₃ (62 g, 0.95 mol) in water (150 mL) was addeddropwise. The solution was then stirred for 2 hours at ambienttemperature. The formed precipitation was collected by filtration andwashed with ice water. The solid was dried to give product 90b (38 g,68% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.00 (s, 1H), 6.47 (s, 1H),3.76 (s, 6H).

(2) Synthesis of LC-10

MeONa (15 g, 0.28 mol) and1-((4-(tert-butyl)phenyl)sulfonyl)propan-2-one (20 g, 79 mmol) wereadded to a solution of compound 90b (17.5 g, 68 mmol) in MeOH. Themixture was stirred at 60° C. overnight and then poured into water. Theprecipitation was collected by filtration. The crude product was washedwith water, followed by MeOH to give product LC-10 (14 g, 42% yield). ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 8.56 (d, 2H, J=8.8 Hz), 8.03 (d, 2H, J=8.8Hz), 7.29 (s, 1H), 6.87 (s, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 2.45 (s,3H), 1.32 (s, 9H). ESI-MS: m/z 494 (M+H)⁺.

iii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(4-chloro-2-methoxy-5-methylphenyl)-5-methyl-1-1,2,3-triazole(LC-19) (1) Synthesis of 90c

NaNO₂ (248 mg, 3.6 mmol) in water (1 mL) was added to a solution of 89c(4-chloro-2-methoxy-5-methylaniline, 513 mg, 3 mmol) in conc. HCl (10mL) at 0° C. and the reaction mixture was then stirred for 15 minutes at0° C. A solution of NaN₃ (234 mg, 3.6 mmol) in water (1 mL) was addeddropwise. The solution was then stirred for 2 hours at ambienttemperature. The reaction mixture was extracted with hexane. The hexanelayer was washed with water, dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor to give product 90c (197 mg, 32% yield).

(2) Synthesis of LC-19

MeONa (108 mg, 2 mmol) and1-((4-(tert-butyl)phenyl)sulfonyl)propan-2-one (254 mg, 1 mmol) wereadded to a solution of compound 90c (197 mg, 1 mmol) in MeOH. Themixture was stirred at 60° C. overnight. The reaction was then pouredinto water and extracted with EtOAc. The EtOAc layer was washed withwater, dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor.The residue was purified by preparative HPLC to give product LC-19 (25mg, 6% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.02 (d, 2H, J=8.8 Hz),7.55 (d, 2H, J=8.8 Hz), 7.17 (s, 1H), 7.06 (s, 1H), 3.76 (s, 3H), 2.42(s, 3H), 2.31 (s, 3H), 1.32 (s, 9H). ESI-MS: m/z 434 (M+H)⁺.

iv. Preparation of1-(4-Bromo-2-Methoxy-5-Methylphenyl)-4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazole(LC-20) (1) Synthesis of 90d

The preparation of compound 90d is similar to the preparation ofcompound 90b except that compound 89d was used as the starting materialto replace compound 89b in the preparation of compound 90b. ¹H NMR (400MHz, CDCl₃) δ (ppm) 7.01 (s, 1H), 6.83 (s, 1H), 3.82 (s, 3H), 2.28 (s,3H).

(2) Synthesis of LC-20

The preparation of LC-20 (70 mg, 14.7% yield) is similar to thepreparation of LC-10 except that compound 90d was used as the startingmaterial to replace compound 90b in the preparation of compound LC-10and the reaction was in a smaller scale (1 mmol scale). ¹H NMR (CDCl₃,400 MHz): δ (ppm) 8.02 (dd, 2H, J=8.8 Hz, 2 Hz), 8.55 (dd, 2H, J=8.8 Hz,2 Hz), 7.24 (s, 1H), 7.17 (s, 1H), 3.76 (s, 3H), 2.42 (s, 3H), 2.34 (s,3H), 1.32 (s, 9H). ESI-MS: m/z 478 (M+H)⁺.

v. Preparation of1-(4-bromo-5-chloro-2-methoxyphenyl)-4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazole(LC-29) (1) Synthesis of 90e

The preparation of 90e is similar to the preparation of 90b except thatcompound 89e was used as the starting material to replace compound 89bin the preparation of compound 90b. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.07(s, 1H), 7.03 (s, 1H), 3.85 (s, 3H).

(2) Synthesis of LC-29

The preparation of LC-29 (75 mg, 15.1% yield) is similar to thepreparation of LC-10 except that compound 90e was used as the startingmaterial to replace compound 90b in the preparation of compound LC-10and the reaction was in a smaller scale (1 mmol scale). ¹H NMR (CDCl₃,400 MHz): δ (ppm) 8.03 (d, 2H, J=8.4 Hz), 8.57 (d, 2H, J=8.4 Hz), 7.43(s, 1H), 7.34 (s, 1H), 3.82 (s, 3H), 2.45 (s, 3H), 1.34 (s, 9H). ESI-MS:m/z 498 (M+H)⁺.

b. General Synthesis of Compounds LC-9, LC-28, LC-64, and LC-65

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(4-chloro-2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole(LC-9) and4-((4-(tert-butyl)phenyl)sulfonyl)-5-(chloromethyl)-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole(LC-64)

n-BuLi (0.24 mL, 0.6 mmol) was added dropwise to solution of compoundLC-10 (300 mg, 0.6 mmol) in THF (5 mL) at −78° C. with stirring. Themixture was stirred for 5 min and then C₂Cl₆ (430 mg, 1.8 mmol) in THF(2 mL) was added, followed by stirring for 1 more hour. The reaction wasquenched with aqueous NH₄Cl and extracted with EtOAc. The EtOAc layerwas washed with water, dried with anhydrous Na₂SO₄ and concentrated witha Rotavapor. The residue was purified by preparative HPLC to giveproduct LC-9 (30 mg, 11% yield) and LC-64 (25 mg, 4% yield). LC-9 ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 7.98 (d, 2H, J=8.4 Hz), 7.51 (d, 2H, J=8.4Hz), 7.07 (s, 1H), 6.85 (s, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 2.39 (s,3H), 1.27 (s, 9H). ESI-MS: m/z 450 (M+H)⁺. LC-64 ¹H NMR (CDCl₃, 400MHz): δ (ppm) 8.10 (d, 2H, J=8.8 Hz), 7.59 (d, 2H, J=8.8 Hz), 7.11 (dd,1H, J=8.8 Hz, 2.8 Hz), 7.03 (d, 1H, J=8.8 Hz), 6.95 (d, 1H, J=2.8 Hz),3.90 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 1.34 (s, 9H). ESI-MS: m/z 450(M+H)⁺.

ii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(4,5-dichloro-2-methoxyphenyl)-5-methyl-1H-1,2,3-triazole(LC-28)

The preparation of LC-28 (38 mg, 14% yield) is similar to thepreparation of LC-9 except that LC-29 was used as the starting materialto replace LC-10 in the preparation of LC-9. ¹H NMR (CDCl₃, 400 MHz): δ(ppm) 7.96 (d, 2H, J=8.4 Hz), 7.51 (d, 2H, J=8.4 Hz), 7.38 (s, 1H), 7.11(s, 1H), 3.75 (s, 3H), 2.39 (s, 3H), 1.27 (s, 9H). ESI-MS: m/z 454(M+H)⁺.

iii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-5-(chloromethyl)-1-(2-methoxy-5-methylphenyl)-1H-1,2,3-triazole(LC-65)

The preparation of LC-65 (80 mg, 30.8% yield) is similar to thepreparation of LC-9 except that LC-20 was used as the starting materialto replace LC-10 in the preparation of LC-9. ¹H NMR (CDCl₃, 400 MHz): δ(ppm) 8.03 (d, 2H, J=8.8 Hz), 7.52 (d, 2H, J=8.8 Hz), 7.29 (d, 1H, J=8.4Hz), 7.12 (s, 1H), 6.92 (d, 1H, J=8.4 Hz), 4.81 (s, 2H), 3.70 (s, 3H),2.27 (s, 3H), 1.28 (s, 9H). ESI-MS: m/z 434 (M+H)⁺.

a. General Synthesis of Compounds LC-11, LC-21, and LC-30

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxy-4-methylphenyl)-5-methyl-1H-1,2,3-triazole(LC-11)

MeB(OH)₂ (50 mg, 0.8 mmol), Pd(PPh₃)₄ (30 mg, 0.03 mmol) and aqueousNa₂CO₃ solution (0.5 mL, 1 mol) were added to a solution of compoundLC-10 (0.3 g, 0.6 mmol) in dioxane (5 mL). The reaction was then stirredfor 5 hours at 120° C. The reaction was then poured into water andextracted with EtOAc. The EtOAc layer was washed with water, dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative HPLC to give product LC-11 (50 mg, 19% yield).¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.98 (d, 2H, J=8.8 Hz), 7.50 (d, 2H,J=8.8 Hz), 6.82 (s, 1H), 6.69 (s, 1H), 3.70 (s, 3H), 3.66 (s, 3H), 2.38(s, 3H), 2.22 (s, 3H), 1.27 (s, 9H). m/z 430 (M+H)⁺.

ii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2-methoxy-4,5-dimethylphenyl)-5-methyl-1H-1,2,3-triazole(LC-21)

MeB(OH)₂ (50 mg, 0.8 mmol), Pd(PPh₃)₄ (30 mg, 0.03 mmol) and aqueousNa₂CO₃ solution (0.5 mL, 1 mol) were added to a solution of compoundLC-20 (0.29 g, 0.6 mmol) in dioxane (5 mL). The reaction was thenstirred for 5 hours at 120° C. The reaction was then poured into waterand extracted with EtOAc. The EtOAc layer was washed with water, driedwith anhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative HPLC to give product LC-21 (150 mg, 60.5%yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.02 (d, 2H, J=8.8 Hz), 7.55(d, 2H, J=8.8 Hz), 7.03 (s, 1H), 6.82 (s, 1H), 3.73 (s, 3H), 2.41 (s,3H), 2.31 (s, 3H), 2.19 (s, 3H), 1.32 (s, 9H). m/z 414 (M+H)⁺.

iii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(5-chloro-2-methoxy-4-methylphenyl)-5-methyl-1H-1,2,3-triazole(LC-30)

MeB(OH)₂ (50 mg, 0.8 mmol), Pd(PPh₃)₄ (30 mg, 0.03 mmol) and aqueousNa₂CO₃ solution (0.5 mL, 1 mol) were added to a solution of compoundLC-29 (0.3 g, 0.6 mmol) in dioxane (5 mL). The reaction was then stirredfor 5 hours at 120° C. The reaction was then poured into water andextracted with EtOAc. The EtOAc layer was washed with water, dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative HPLC to give product LC-30 (135 mg, 51.9%yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.01 (d, 2H, J=8.8 Hz), 7.55(d, 2H, J=8.8 Hz), 7.29 (s, 1H), 6.92 (s, 1H), 3.76 (s, 3H), 2.43 (s,6H), 1.32 (s, 9H). m/z 434 (M+H)⁺.

b. General Synthesis of Compounds LC-12, LC-22, and LC-31

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(4-ethyl-2,5-dimethoxyphenyl)-5-methyl-1-1,2,3-triazole(LC-12) (1) Synthesis of 91a

EthenylSn(Bu)₃ (385 mg, 1.2 mmol) and Pd(PPh₃)₄ (70 mg, 0.06 mmol) wasadded to a solution of compound LC-10 (0.3 g, 0.6 mmol) in toluene (5mL). The reaction was stirred for 5 hours at 120° C. The reaction wasthen poured into water and extracted with EtOAc. The EtOAc layer waswashed with water, dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by preparative HPLC to give product91a (85 mg, 32% yield). m/z 442 (M+H)⁺.

(2) Synthesis of LC-12

10% Pd/C (10 mg) was added to a solution of compound 91a (85 mg, 0.20mmol) in MeOH/THF (5 mL/5 mL). Bubbled with H₂ gas, the reaction mixturewas stirred for 3 hours at room temperature. The reaction mixture wasthen filtered and the filtrate was concentrated with a Rotavapor. Theresidue was purified by preparative HPLC to give product LC-12 (65 mg,76% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.98 (d, 2H, J=8.8 Hz),7.50 (d, 2H, J=8.8 Hz), 6.81 (s, 1H), 6.70 (s, 1H), 3.69 (s, 3H), 3.67(s, 3H), 2.65-2.59 (m, 2H), 2.39 (s, 3H), 1.27 (s, 9H), 1.14 (t, 3H,J=7.6 Hz). m/z 444 (M+H)⁺.

ii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(4-ethyl-2-methoxy-5-methylphenyl)-5-methyl-1H-1,2,3-triazole(LC-22)

The preparation of compound LC-22 (60 mg, 23.4% yield) was similar tothe preparation of compound LC-12 except that compound LC-20 was used asthe starting material to replace LC-10 in the preparation of LC-12. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 7.97 (d, 2H, J=8.4 Hz), 7.49 (d, 2H, J=8.4Hz), 6.99 (s, 1H), 6.77 (s, 1H), 3.68 (s, 3H), 2.63-2.57 (m, 2H), 2.37(s, 3H), 2.18 (s, 3H), 1.27 (s, 9H), 1.18 (t, 3H, J=7.2 Hz). m/z 428(M+H)⁺.

iii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(5-chloro-4-ethyl-2-methoxyphenyl)-5-methyl-1H-1,2,3-triazole(LC-31)

The preparation of compound LC-31 (41 mg, 15.3% yield) was similar tothe preparation of compound LC-12 except that compound LC-29 was used asthe starting material to replace LC-10 in the preparation of LC-12. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 7.97 (d, 2H, J=8.4 Hz), 7.50 (d, 2H, J=8.4Hz), 7.25 (s, 1H), 6.86 (s, 1H), 3.73 (s, 3H), 2.77-2.71 (m, 2H), 2.37(s, 3H), 1.23 (s, 9H), 1.19 (t, 3H, J=6.0 Hz). m/z 448 (M+H)⁺.

c. General Synthesis of LC-13, LC-23, and LC-32

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(4-isopropyl-2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole(LC-13) (1) Synthesis of 92a

4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (340 mg, 2mmol), Pd(PPh₃)₄ (117 mg, 0.1 mmol) and Na₂CO₃ aq. (0.5 mL, 1 mol) wereadded to a solution of compound LC-10 (500 mg, 1.0 mmol) and thereaction was stirred for 5 hours at 120° C. The reaction was then pouredinto water and extracted with EtOAc. The EtOAc layer was washed withwater, dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor.The residue was purified by preparative HPLC to give product 92a (110mg, 24% yield). m/z 456 (M+H)⁺.

(2) Synthesis of LC-13

10% Pd/C (10 mg) was added to a solution of compound 92a (110 mg, 0.24mmol) in MeOH/THF (5 mL/5 mL). Bubbled with H₂ gas, the reaction mixturewas stirred for 3 hours at room temperature. The reaction mixture wasthen filtered and the filtrate was concentrated with a Rotavapor. Theresidue was purified by preparative HPLC to give product LC-13 (100 mg,91% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.03 (d, 2H, J=8.4 Hz),7.55 (d, 2H, J=8.4 Hz), 6.90 (s, 1H), 6.75 (s, 1H), 3.74 (s, 3H), 3.72(s, 3H), 3.38-3.31 (m, 1H), 2.45 (s, 3H), 1.32 (s, 9H), 1.22 (d, 6H,J=6.8 Hz). m/z 458 (M+H)⁺.

ii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(4-isopropyl-2-methoxy-5-methylphenyl)-5-methyl-1H-1,2,3-triazole(LC-23)

The preparation of compound LC-23 (140 mg, 15.9% yield for 2 steps) wassimilar to the preparation of compound LC-13 except that compound LC-20was used as the starting material to replace LC-10 in the preparation ofLC-13. ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.97 (d, 2H, J=8.4 Hz), 7.50 (d,2H, J=8.4 Hz), 6.98 (s, 1H), 6.89 (s, 1H), 3.74 (s, 3H), 3.41-3.34 (m,1H), 2.40 (s, 3H), 1.27 (s, 9H), 1.22 (d, 6H, J=6.8 Hz). m/z 442 (M+H)⁺.

iii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(5-chloro-4-isopropyl-2-methoxyphenyl)-5-methyl-1H-1,2,3-triazole(LC-32)

The preparation of compound LC-32 (31 mg, 3.4% yield for 2 steps) wassimilar to the preparation of compound LC-13 except that compound LC-29was used as the starting material to replace LC-10 in the preparation ofLC-13. ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.97 (d, 2H, J=8.4 Hz), 7.50 (d,2H, J=8.4 Hz), 7.25 (s, 1H), 6.83 (s, 1H), 3.70 (s, 3H), 3.13-3.06 (m,1H), 2.38 (s, 3H), 2.21 (s, 3H), 1.27 (s, 9H), 1.19 (d, 6H, J=6.8 Hz).m/z 462 (M+H)⁺.

d. General Synthesis of LC-14, LC-24, and LC-33

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(5-chloro-2,4-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole(LC-33)

MeONa (130 mg, 2.4 mmol) and CuCl₂ (119 mg, 1.2 mmol) were added to asolution of compound LC-29 (300 mg, 0.6 mmol) in DMF (10 mL). Thereaction was stirred overnight at 130° C. The reaction was then pouredinto water and extracted with EtOAc. The EtOAc layer was washed withwater, dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor.The residue was purified by preparative HPLC to give product LC-33 (60mg, 22% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.01 (d, 2H, J=8.4 Hz),7.55 (d, 2H, J=8.4 Hz), 7.31 (s, 1H), 6.58 (s, 1H), 3.97 (s, 3H), 3.80(s, 3H), 2.42 (s, 3H), 1.32 (s, 9H). m/z 450 (M+H)⁺.

ii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1-(2,4,5-trimethoxyphenyl)-1H-1,2,3-triazole(LC-14)

The preparation of compound LC-14 (36 mg, 13.4% yield) was similar tothe preparation of compound LC-33 except that compound LC-10 was used asthe starting material to replace LC-29 in the preparation of LC-33. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 7.98 (d, 2H, J=8.4 Hz), 7.50 (d, 2H, J=8.4Hz), 6.75 (s, 1H), 6.55 (s, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 3.69 (s,3H), 2.38 (s, 3H), 1.27 (s, 9H). m/z 446 (M+H)⁺.

iii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,4-dimethoxy-5-methylphenyl)-5-methyl-1H-1,2,3-triazole(LC-24)

The preparation of compound LC-24 (30 mg, 11.7% yield) was similar tothe preparation of compound LC-33 except that compound LC-20 was used asthe starting material to replace LC-29 in the preparation of LC-33. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 7.97 (d, 2H, J=8.4 Hz), 7.49 (d, 2H, J=8.4Hz), 6.97 (s, 1H), 6.44 (s, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 2.36 (s,3H), 2.08 (s, 3H), 1.27 (s, 9H). m/z 430 (M+H)⁺.

e. General Synthesis of LC-15, LC-25, and LC-34

i. Preparation of methyl4-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-2,5-dimethoxybenzoate(LC-15)

A mixture of compound LC-10 (250 mg, 0.5 mmol) and Pd(dppf)Cl₂ (41 mg,0.05 mmol) in MeOH (10 mL) was stirred at 80° C. under CO (1.5 MPa) for24 hours. The reaction was then cooled and the mixture was concentratedwith a Rotavapor. The residue was purified by preparative HPLC to giveproduct LC-15 (80 mg, 33% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 0.98(d, 2H, J=8.8 Hz), 7.51 (d, 2H, J=8.8 Hz), 7.44 (s, 1H), 6.92 (s, 1H),3.87 (s, 3H), 3.78 (s, 3H), 3.73 (s, 3H), 2.41 (s, 3H), 1.27 (s, 9H).m/z 474 (M+H)⁺.

ii. Preparation of methyl4-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-5-methoxy-2-methylbenzoate(LC-25)

The preparation of compound LC-25 (54 mg, 23.6% yield) was similar tothe preparation of compound LC-15 except that compound LC-20 was used asthe starting material to replace LC-10 in the preparation of LC-15. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 8.02 (d, 2H, J=8.4 Hz), 7.75-7.78 (m, 3H),7.21 (s, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 2.52 (s, 3H), 2.44 (s, 3H),1.32 (s, 9H). m/z 458 (M+H)⁺.

iii. Preparation of methyl4-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-2-chloro-5-methoxybenzoate(LC-34)

The preparation of compound LC-34 (105 mg, 44% yield) was similar to thepreparation of compound LC-15 except that compound LC-29 was used as thestarting material to replace LC-10 in the preparation of LC-15. ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 8.01 (d, 2H, J=8.4 Hz), 7.56 (d, 2H, J=8.4Hz), 7.50 (s, 1H), 7.44 (s, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 2.45 (s,3H), 1.32 (s, 9H). m/z 478 (M+H)⁺.

f. General Synthesis of LC-17, LC-27, and LC-36

i. Preparation of4-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-2,5-dimethoxybenzonitrile(LC-17)

Zn(CN)₂ (423 mg, 3.6 mmol) and Pd(dppf)Cl₂ (88 mg, 0.12 mmol) were addedto a solution of LC-10 (600 mg, 1.2 mmol) in DMF (10 mL). The reactionwas stirred for 15 min at 160° C. under microwave. The reaction was thenpoured into water and extracted with EtOAc. The EtOAc layer was washedwith water, dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by preparative HPLC to give productLC-17 (280 mg, 53% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.63 (d, 2H,J=8.8 Hz), 8.09 (d, 2H, J=8.8 Hz), 7.31 (s, 1H), 7.05 (s, 1H), 3.94 (s,3H), 3.85 (s, 3H), 2.53 (s, 3H), 1.39 (s, 9H). m/z 441 (M+H)⁺.

ii. Preparation of4-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-5-methoxy-2-methylbenzonitrile(LC-27)

The preparation of compound LC-27 (52 mg, 10.2% yield) was similar tothe preparation of compound LC-17 except that compound LC-20 was used asthe starting material to replace LC-10 in the preparation of LC-17. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 7.97 (d, 2H, J=8.4 Hz), 7.51 (d, 2H, J=8.4Hz), 7.25 (s, 1H), 7.19 (s, 1H), 3.77 (s, 3H), 2.46 (s, 3H), 2.39 (s,3H), 1.27 (s, 9H). m/z 425 (M+H)⁺.

iii. Preparation of4-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-2-chloro-5-methoxybenzonitrile(LC-36)

The preparation of compound LC-36 (60 mg, 11.3% yield) was similar tothe preparation of compound LC-17 except that compound LC-29 was used asthe starting material to replace LC-10 in the preparation of LC-17. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 8.02 (d, 2H, J=8.4 Hz), 7.57 (d, 2H, J=8.4Hz), 7.53 (s, 1H), 7.34 (s, 1H), 3.87 (s, 3H), 2.47 (s, 3H), 1.33 (s,9H). m/z 445 (M+H)⁺.

g. General Synthesis of LC-16, LC-26, and LC-35

i. Preparation of1-(4-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-2,5-dimethoxyphenyl)ethan-1-one(LC-16)

A solution of MeMgBr (0.2 mL, 1.5 mmol) in THF was added to a solutionof compound LC-17 (100 mg, 0.2 mmol) in THF (30 mL). The reaction wasunder reflux for 15 hours. The reaction was then cooled. HCl (1 mL, 1N)was added and the mixture was stirred for another 2 hours. The reactionwas then poured into water and extracted with EtOAc. The EtOAc layer waswashed with water, dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by preparative HPLC to give productLC-16 (60 mg, 58% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.99 (d, 2H,J=8.8 Hz), 7.52 (d, 2H, J=8.8 Hz), 7.41 (s, 1H), 6.93 (s, 1H), 3.81 (s,3H), 3.74 (s, 3H), 2.60 (s, 3H), 2.42 (s, 3H), 1.28 (s, 9H). m/z 458(M+H)⁺.

ii. Preparation of1-(4-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-5-methoxy-2-methylphenyl)ethan-1-one(LC-26)

The preparation of compound LC-26 (80 mg, 90.7% yield) was similar tothe preparation of compound LC-16 except that compound LC-27 was used asthe starting material to replace LC-17 in the preparation of LC-16. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 8.02 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz,2H), 7.20-7.24 (m, 2H), 3.82 (s, 3H), 2.60 (s, 3H), 2.44 (s, 3H), 2.42(s, 3H), 1.33 (s, 9H). m/z 442 (M+H)⁺.

iii. Preparation of1-(4-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-2-chloro-5-methoxyphenyl)ethan-1-one(LC-35)

The preparation of compound LC-35 (53 mg, 57.5% yield) was similar tothe preparation of compound LC-16 except that compound LC-29 was used asthe starting material to replace LC-17 in the preparation of LC-16. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 8.02 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz,2H), 7.24 (s, 1H), 7.21 (s, 1H), 3.82 (s, 3H), 2.70 (s, 3H), 2.46 (s,3H), 1.33 (s, 9H). m/z 462 (M+H)⁺.

h. General Synthesis of LC-18 and LC-63

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(4-fluoro-2-methoxy-5-methylphenyl)-5-methyl-1H-1,2,3-triazole(LC-18)

n-BuLi (0.4 mL, 1 mmol) was added dropwise to solution of compound LC-20(477 mg, 1 mmol) in THF (5 mL) at −78° C. with stirring. The mixture wasstirred for 5 min and then NFSI (409 mg, 1.3 mmol) in THF (2 mL) wasadded, followed by stirring for 1 more hour. The reaction was quenchedwith aqueous NH₄Cl and extracted with EtOAc. The EtOAc layer was washedwith water, dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by preparative HPLC to give productLC-18 (30 mg, 7% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.02 (d, 2H,J=8.4 Hz), 7.55 (d, 2H, J=8.4 Hz), 7.13 (d, 1H, J=7.6 Hz), 6.74 (d, 1H,J=10.4 Hz), 3.74 (s, 3H), 2.42 (s, 3H), 2.21 (d, 3H, J=1.2 Hz), 1.32 (s,9H). ESI-MS: m/z 418 (M+H)⁺.

ii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-(fluoromethyl)-1H-1,2,3-triazole(LC-63)

n-BuLi (0.4 mL, 1 mmol) was added dropwise to solution of compound LC-10(493 mg, 1 mmol) in THF (5 mL) at −78° C. with stirring. The mixture wasstirred for 5 min and then NFSI (409 mg, 1.3 mmol) in THF (2 mL) wasadded, followed by stirring for 1 more hour. The reaction was quenchedwith aqueous NH₄Cl and extracted with EtOAc. The EtOAc layer was washedwith water, dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by preparative HPLC to give productLC-63 (68 mg, 16% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.06 (d, 2H,J=8.4 Hz), 7.58 (d, 2H, J=8.4 Hz), 7.07-7.10 (m, 1H), 7.00-7.03 (m, 1H),6.94 (d, 1H, J=2.8 Hz), 5.65 (d, 2H, J=47.2 Hz), 3.76 (s, 3H), 3.73 (s,3H), 1.33 (s, 9H). ESI-MS: m/z 434 (M+H)⁺.

i. Synthesis of methyl2-(4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2-methoxy-5-methylphenyl)-1H-1,2,3-triazol-5-yl)acetate(LC-66)

n-BuLi (0.24 mL, 0.6 mmol) was added dropwise to solution of compoundLC-20 (300 mg, 0.6 mmol) in THF (5 mL) at −78° C. with stirring. Themixture was stirred for 20 min and then the reaction mixture was pouredinto a cooled (−78° C.) THF solution of Me₂CO₃ (113 mg, 1.2 mmol) andstirred for 2 hours at −78° C. The reaction was quenched with aqueousNH₄Cl and extracted with EtOAc. The EtOAc layer was washed with water,dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by preparative HPLC to give product LC-66 (10 mg,3% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.98 (d, 2H, J=8.8 Hz), 7.51(d, 2H, J=8.8 Hz), 7.25 (d, 1H, J=8.0 Hz), 7.08 (s, 1H), 6.88 (d, 1H,J=8.0 Hz), 3.94 (s, 2H), 3.67 (s, 3H), 3.55 (s, 3H), 2.25 (s, 3H), 1.27(s, 9H). ESI-MS: m/z 458 (M+H)⁺.

j. General Synthesis of Compounds LC-37, LC-38, and LC-39

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazol-5-amine(LC-37)

MeONa (2.2 g, 40 mmol) and 94a³² (4.74 g, 20 mmol) were added to asolution of 2-((4-(tert-butyl)phenyl)sulfonyl)acetonitrile (3.58 g, 20mmol) in MeOH. The mixture was stirred overnight at room temperature.The formed precipitation was collected by filtration. The crude productwas washed with water, MeOH and purified with recrystallization to giveproduct LC-37 (5.12 g, 62% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.98(d, 2H, J=8.4 Hz), 7.53 (d, 2H, J=8.4 Hz), 7.01 (s, 2H), 6.95 (s, 1H),5.20 (s, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 1.31 (s, 9H). m/z 417 (M+H)⁺.

ii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2-methoxy-5-methylphenyl)-1H-1,2,3-triazol-5-amine(LC-38)

The preparation of compound LC-38 (60 mg, 15% yield) was similar to thepreparation of compound LC-37 except that compound 94b³² was used as thestarting material to replace 94a in the preparation of LC-37 and at asmaller scale (1 mmol scale). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.88 (d,2H, J=8.4 Hz), 7.63 (d, 2H, J=8.4 Hz), 7.33 (d, 1H, J=8.4 Hz), 7.17 (s,1H), 7.12 (d, 1H, J=8.4 Hz), 6.39 (s, 2H), 3.70 (s, 3H), 2.23 (s, 3H),1.26 (s, 9H). m/z 401 (M+H)⁺.

iii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(5-chloro-2-methoxyphenyl)-1H-1,2,3-triazol-5-amine(LC-39)

The preparation of compound LC-39 (60 mg, 14.3% yield) was similar tothe preparation of compound LC-37 except that compound 94c³² was used asthe starting material to replace 94a in the preparation of LC-37 and ata smaller scale (1 mmol scale). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.96(d, 2H, J=8.4 Hz), 7.53 (d, 2H, J=8.4 Hz), 7.38-7.45 (m, 2H), 7.02 (d,1H, J=9.2 Hz), 5.18 (br, 2H), 3.86 (s, 3H), 1.31 (s, 9H). m/z 421(M+H)⁺.

k. General Synthesis of 95b, LC-61, and LC-62

i. Preparation of5-bromo-4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole(LC-61, 95a)

t-BuNO₂ (683 mg, 6.64 mmol) was added dropwise to a solution of LC-37(2.3 g, 5.53 mmol) and CuBr₂ (1.85 g, 8.3 mmol) in CH₃CN (25 mL) underN₂ and room temperature. The reaction was stirred under this conditionfor 3 hours. H₂O (25 mL) was added and the mixture was extracted withEtOAc (25 mL×2). The combined EtOAc layers were dried with anhydrousNa₂SO₄ and concentrated with a Rotavapor. The residue was purified bysilica gel chromatography (Petroleum Ether/EtOAc=10/1 to 6/1) to giveproduct LC-61 (95a, 1.0 g, 37.7% yield). ¹H NMR (CDCl₃, 400 MHz): δ(ppm) 8.06 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 6.84-7.00 (m, 3H),3.77 (s, 3H), 3.74 (s, 3H), 1.33 (s, 9H). m/z 480 (M+H)⁺.

ii. Preparation of5-bromo-4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2-methoxy-5-methylphenyl)-1H-1,2,3-triazole(95b)

t-BuNO₂ (683 mg, 6.64 mmol) was added dropwise to a solution of LC-38(1.9 g, 4.75 mmol) and CuBr₂ (1.59 g, 7.12 mmol) in CH₃CN (20 mL) underN₂ and room temperature. The reaction was stirred under this conditionfor 2 hours. H₂O (20 mL) was added and the mixture was extracted withEtOAc (15 mL×3). The combined EtOAc layers were dried with anhydrousNa₂SO₄ and concentrated with a Rotavapor. The residue was purified bysilica gel chromatography (Petroleum Ether/EtOAc=10/1 to 6/1) to giveproduct 95b (1.0 g, 37.7% yield). m/z 464 (M+H)⁺.

iii. Preparation of5-bromo-4-((4-(tert-butyl)phenyl)sulfonyl)-1-(5-chloro-2-methoxyphenyl)-1H-1,2,3-triazole(LC-62, 95c)

t-BuNO₂ (352 mg, 3.42 mmol) was added dropwise to a solution of LC-39(1.2 g, 2.85 mmol) and CuBr₂ (0.95 g, 4.3 mmol) in CH₃CN (15 mL) underN₂ and room temperature. The reaction was stirred under this conditionfor 2 hours. H₂O (15 mL) was added and the mixture was extracted withEtOAc (15 mL×3). The combined EtOAc layers were dried with anhydrousNa₂SO₄ and concentrated with a Rotavapor. The residue was purified bysilica gel chromatography (Petroleum Ether/EtOAc=10/1 to 6/1) to giveproduct LC-62 (95c, 0.6 g, 43.8% yield). ¹H NMR (CDCl₃, 400 MHz): δ(ppm) 8.06 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz,1H), 7.30 (s, 1H), 7.01 (d, J=8.4 Hz, 1H), 3.79 (s, 3H), 1.33 (s, 9H).m/z 484 (M+H)⁺.

l. General Synthesis of LC-49, LC-50, LC-51, LC-61, and LC-62

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole-5-carbonitrile(LC-49)

A suspension of compound LC-61 (95a, 1.0 g, 2.1 mmol), KCN (1.36 g, 21mmol) and CuCN (934 mg, 10.5 mmol) in DMF (15 mL) was heated at 110° C.for 19 hours under N₂. EtOAc (30 mL) was then added to the reaction andthe mixture was washed with brine, dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by preparativeHPLC to give product LC-49 (180 mg, 20.1% yield). ¹H NMR (CDCl₃, 400MHz): δ (ppm) 8.11 (d, J=6.8 Hz, 2H), 7.61 (d, J=6.8 Hz, 2H), 7.00-7.13(m, 3H), 3.85 (s, 3H), 3.78 (s, 3H), 1.34 (s, 9H). m/z 427 (M+H)⁺.

ii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2-methoxy-5-methylphenyl)-1H-1,2,3-triazole-5-carbonitrile(LC-50)

A suspension of compound 95b (400 mg, 0.86 mmol), KCN (559 mg, 8.6 mmol)and CuCN (382 mg, 4.3 mmol) in DMF (6 mL) was heated at 110° C. for 19hours under N₂. EtOAc (15 mL) was then added to the reaction and themixture was washed with brine, dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by preparativeHPLC to give product LC-50 (53 mg, 15.0% yield). ¹H NMR (CDCl₃, 400MHz): δ (ppm) 8.09 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.36 (d,J=8.4 Hz, 1H), 7.24 (s, 1H), 7.01 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 2.33(s, 3H), 1.33 (s, 9H). m/z 411 (M+H)⁺.

iii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(5-chloro-2-methoxyphenyl)-1H-1,2,3-triazole-5-carbonitrile(LC-51)

A suspension of compound LC-62 (95c, 600 mg, 1.24 mmol), KCN (807 mg,12.4 mmol) and CuCN (331 mg, 3.72 mmol) in DMF (7 mL) was heated at 110°C. for 19 hours under N₂. EtOAc (30 mL) was then added to the reactionand the mixture was washed with brine, dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by preparativeHPLC to give product LC-51 (160 mg, 30.0% yield). ¹H NMR (CDCl₃, 400MHz): δ (ppm) 8.10 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.54 (t,J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.09 (d, J=8.8 Hz,1H), 3.90 (s, 3H), 1.33 (s, 9H). m/z 431 (M+H)⁺.

m. General Synthesis of LC-52, LC-53, and LC-54

i. Preparation of1-(4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazol-5-yl)ethan-1-one(LC-52)

A suspension of compound LC-61 (95a, 400 mg, 0.835 mmol),tributyl(1-ethoxyvinyl)stannane (361 mg, 1.0 mmol), Pd(PPh₃)₄ (96 mg,0.0835 mmol) in toluene (8 mL) was heated to 110° C. for 3 hours underN₂. After cooled down, concentrated HCl/dioxane (8 mL) was added. Thesolution was stirred at room temperature for 1 hour. H₂O (15 mL) wasadded and the mixture was extracted with EtOAc (15 mL×3). The combinedEtOAc organic layers were dried with anhydrous Na₂SO₄ and concentratedwith a Rotavapor. The residue was purified by preparative HPLC to givethe product LC-52 (55 mg, 14.9% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm)8.04 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 6.96-7.04 (m, 3H), 3.76(s, 3H), 3.71 (s, 3H), 2.76 (s, 3H), 1.34 (s, 9H). m/z 444 (M+H)⁺.

ii. Preparation of1-(4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2-methoxy-5-methylphenyl)-1H-1,2,3-triazol-5-yl)ethan-1-one(LC-53)

A suspension of compound 95b (300 mg, 0.64 mmol),tributyl(1-ethoxyvinyl)stannane (281 mg, 0.78 mmol), Pd(PPh₃)₄ (74 mg,0.064 mmol) in toluene (6 mL) was heated to 110° C. for 3 hours underN₂. After cooled down, concentrated HCl/dioxane (7 mL) was added. Thesolution was stirred at room temperature for 1 hour. H₂O (15 mL) wasadded and the mixture was extracted with EtOAc (10 mL×3). The combinedEtOAc organic layers were dried with anhydrous Na₂SO₄ and concentratedwith a Rotavapor. The residue was purified by preparative HPLC to givethe product LC-53 (80 mg, 29.3% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm)8.04 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.23-7.24 (m, 2H), 6.88(d, J=8.4 Hz, 1H), 3.75 (s, 3H), 2.75 (s, 3H), 2.32 (s, 3H), 1.34 (s,9H). m/z 428 (M+H)⁺.

iii. Preparation of1-(4-((4-(tert-butyl)phenyl)sulfonyl)-1-(5-chloro-2-methoxyphenyl)-1H-1,2,3-triazol-5-yl)ethan-1-one(LC-54)

A suspension of compound LC-62 (95c, 350 mg, 0.72 mmol),tributyl(1-ethoxyvinyl)stannane (314 mg, 0.87 mmol), Pd(PPh₃)₄ (83 mg,0.072 mmol) in toluene (6 mL) was heated to 110° C. for 3 hours underN₂. After cooled down, concentrated HCl/dioxane (6 mL) was added. Thesolution was stirred at room temperature for 1 hour. H₂O (15 mL) wasadded and the mixture was extracted with EtOAc (10 mL×3). The combinedEtOAc organic layers were dried with anhydrous Na₂SO₄ and concentratedwith a Rotavapor. The residue was purified by preparative HPLC to givethe product LC-54 (35 mg, 10.9% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm)8.02 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.42-7.49 (m, 2H), 6.93(d, J=8.4 Hz, 1H), 3.77 (s, 3H), 2.81 (s, 3H), 1.34 (s, 9H). m/z 448(M+H)⁺.

n. General Synthesis of LC-55, LC-56, and LC-57

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-ethyl-1H-1,2,3-triazole(LC-55)

MeONa (108 mg, 2 mmol) and 94a³² (179 mg, 1 mmol) were added to asolution of 1-((4-(tert-butyl)phenyl)sulfonyl)butan-2-one (268 mg, 1mmol) in MeOH. The mixture was stirred at 60° C. overnight. H₂O (15 mL)was added and the mixture was extracted with EtOAc (15 mL×3). Thecombined EtOAc organic layers were dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by preparativeHPLC to give the product LC-55 (55 mg, 13% yield). ¹H NMR (CDCl₃, 400MHz): δ (ppm) 8.05 (d, 2H, J=8.4 Hz), 7.57 (d, 2H, J=8.4 Hz), 7.06-7.09(m, 1H), 6.99-7.01 (m, 1H), 6.84 (d, 1H, J=2.8 Hz), 3.77 (s, 3H), 3.72(s, 3H), 2.89-2.91 (m, 2H), 1.34 (s, 9H), 1.09 (t, 3H, J=7.6 Hz). m/z430 (M+H)⁺.

ii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-5-ethyl-1-(2-methoxy-5-methylphenyl)-1H-1,2,3-triazole(LC-56)

The preparation of compound LC-56 (51 mg, 12.3% yield) was similar tothe preparation of compound LC-55 except that compound 94b³² was used asthe starting material to replace 94a in the preparation of LC-55. ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 7.99 (d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8Hz), 7.25 (d, 1H, J=8.4 Hz), 7.02 (s, 1H), 6.89 (d, 1H, J=8.4 Hz), 3.67(s, 3H), 2.81 (s, 2H), 2.26 (s, 3H), 1.27 (s, 9H), 1.02 (t, 3H, J=7.6Hz). m/z 414 (M+H)⁺.

iii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(5-chloro-2-methoxyphenyl)-5-ethyl-1H-1,2,3-triazole(LC-57)

The preparation of compound LC-57 (94 mg, 21.7% yield) was similar tothe preparation of compound LC-55 except that compound 94c³² was used asthe starting material to replace 94a in the preparation of LC-55. ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 8.04 (d, 2H, J=8.4 Hz), 7.57 (d, 2H, J=8.4Hz), 7.49-7.52 (m, 1H), 7.30 (s, 1H), 7.02 (d, 1H, J=8.8 Hz), 3.78 (s,3H), 2.88-2.90 (m, 2H), 1.34 (s, 9H), 1.09 (t, 3H, J=7.6 Hz). m/z 434(M+H)⁺.

o. General Synthesis of Compounds LC-58, LC-59, and LC-60

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole(LC-58)

NaNO₂ (83 mg, 1.2 mmol) was added to a solution of LC-37 (416 mg, 1mmol) in 20 mL EtOH and 2 mL H₂SO₄. The reaction was then stirred at 50°C. for 4 hours. H₂O (25 mL) was added and the mixture was extracted withEtOAc (25 mL×3). The combined EtOAc layers were dried with anhydrousNa₂SO₄ and concentrated with a Rotavapor. The residue was purified bypreparative HPLC to give product LC-58 (98 mg, 24% yield). ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 8.74 (s, 1H), 8.03 (d, 2H, J=8.4 Hz), 7.55 (d,2H, J=8.4 Hz), 7.37 (d, 1H, J=2.8 Hz), 6.95-7.02 (m, 2H), 3.86 (s, 3H),3.77 (s, 3H), 1.31 (s, 9H). m/z 402 (M+H)⁺.

ii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2-methoxy-5-methylphenyl)-1H-1,2,3-triazole(LC-59)

The preparation of compound LC-59 (50 mg, 10.8% yield) was similar tothe preparation of compound LC-58 except that compound LC-38 was used asthe starting material to replace LC-37 in the preparation of LC-58. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 8.67 (s, 1H), 8.03 (d, 2H, J=8.8 Hz),7.53-7.58 (m, 3H), 7.21-7.24 (m, 1H), 6.96 (d, 1H, J=8.4 Hz), 3.86 (s,3H), 2.32 (s, 3H), 1.31 (s, 9H). m/z 386 (M+H)⁺.

iii. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(5-chloro-2-methoxyphenyl)-1-1,2,3-triazole(LC-60)

The preparation of compound LC-60 (96 mg, 19.8% yield) was similar tothe preparation of compound LC-58 except that compound LC-39 was used asthe starting material to replace LC-37 in the preparation of LC-58. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 8.70 (s, 1H), 8.02 (d, 2H, J=8.8 Hz), 7.83(d, 1H, J=2.4 Hz), 7.55 (d, 2H, J=8.8 Hz), 7.38-7.41 (m, 1H), 7.03 (d,1H, J=9.2 Hz), 3.92 (s, 3H), 1.31 (s, 9H). m/z 406 (M+H)⁺.

p. General Synthesis of LC-40, LC-41, and LC-42

i. Preparation of(4-(tert-butyl)phenyl)(1-(2,5-dimethoxyphenyl)-5-methyl-1-1,2,3-triazol-4-yl)methanone(LC-40) (1) Synthesis of 97a

O,N-Dimethyl-hydroxylamine (221 mg, 2.28 mmol) was added to a solutionof compound1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid(96a, 500 mg, 1.9 mmol), HATU (866 mg, 2.28 mmol), TEA (767 mg, 7.6mmol) in DCM (15 mL) and the reaction was stirred at room temperaturefor 2 hours. The mixture was washed with H₂O (15 mL) and organic layerwas dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by preparative TLC (Petroleum Ether/EtOAc=1/1) togive the product 97a (500 mg, 86.2% yield). m/z 307 (M+H)⁺.

(2) Synthesis of LC-40

n-BuLi (1.17 mL, 2.94 mmol) was added to 1-bromo-4-tert-butyl-benzene(623 mg, 2.94 mmol) in THF (10 mL) at −78° C. and the solution was thenstirred at −70° C. for 2 hours. A solution of compound 97a (500 mg, 0.98mmol) in THF (6 mL) was added dropwise with the reaction temperaturemaintained below 5° C. The result mixture was stirred at roomtemperature for 1 hour. H₂O (10 mL) was added and the mixture wasextracted with EtOAc (10 mL×2). The combined EtOAc organic layers weredried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by preparative HPLC to give the product LC-40 (130mg, 35% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.32 (d, J=8.4 Hz, 2H),7.52 (d, J=8.4 Hz, 2H), 7.00-7.01 (m, 2H), 6.96 (s, 1H), 3.80 (s, 3H),3.75 (s, 3H), 2.50 (s, 3H), 1.35 (s, 9H). m/z 380 (M+H)⁺.

ii. Preparation of(4-(tert-butyl)phenyl)(1-(2-methoxy-5-methylphenyl)-5-methyl-1-1,2,3-triazol-4-yl)methanone(LC-41) (1) Synthesis of 97b

O,N-Dimethyl-hydroxylamine (188 mg, 1.94 mmol) was added to a solutionof compound1-(2-methoxy-5-methylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylicacid (96b, 400 mg, 1.62 mmol), HATU (862 mg, 2.07 mmol), TEA (0.9 mL,6.48 mmol) in DCM (15 mL) and the reaction was stirred at roomtemperature for 2 hours. The mixture was washed with H₂O (15 mL) andorganic layer was dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by preparative TLC (PetroleumEther/EtOAc=1/1) to give the product 97b (400 mg, 86.2% yield). m/z 291(M+H)⁺.

(2) Synthesis of LC-41

n-BuLi (1.1 mL, 2.76 mmol) was added to 1-bromo-4-tert-butyl-benzene(585 mg, 2.76 mmol) in THF (8 mL) at −78° C. and the solution was thenstirred at −70° C. for 1 hour. A solution of compound 97b (400 mg, 1.38mmol) in THF (8 mL) was added dropwise with the reaction temperaturemaintained below 5° C. The result mixture was stirred at roomtemperature for 1 hour. H₂O (20 mL) was added and the mixture wasextracted with EtOAc (10 mL×3). The combined EtOAc organic layers weredried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by preparative HPLC to give the product LC-41 (55mg, 11% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.30 (d, J=8.0 Hz, 2H),7.52 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.4 Hz, 1H), 7.21 (S, 1H), 6.97 (d,J=8.4 Hz, 1H), 3.78 (s, 3H), 2.49 (s, 3H), 2.35 (s, 3H), 1.35 (s, 9H).m/z 364 (M+H)⁺.

iii. Preparation of(4-(tert-butyl)phenyl)(1-(5-chloro-2-methoxyphenyl)-5-methyl-1-1,2,3-triazol-4-yl)methanone(LC-42) (1) Synthesis of 97c

O,N-Dimethyl-hydroxylamine (218 mg, 2.24 mmol) was added to a solutionof compound1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylicacid (96c, 500 mg, 1.87 mmol), HATU (1.06 g, 2.8 mmol), TEA (1.03 mL,7.48 mmol) in DCM (15 mL) and the reaction was stirred at roomtemperature for 2 hours. The mixture was washed with H₂O (15 mL) andorganic layer was dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by preparative TLC (PetroleumEther/EtOAc=1/1) to give the product 97c (260 mg, 44.8% yield). m/z 311(M+H)⁺.

(2) Synthesis of LC-42

n-BuLi (1.0 mL, 2.52 mmol) was added to 1-bromo-4-tert-butyl-benzene(534 mg, 2.52 mmol) in THF (10 mL) at −78° C. and the solution was thenstirred at −70° C. for 2 hours. A solution of compound 97c (260 mg, 0.84mmol) in THF (6 mL) was added dropwise with the reaction temperaturemaintained below 5° C. The result mixture was stirred at roomtemperature for 1 hour. H₂O (10 mL) was added and the mixture wasextracted with EtOAc (10 mL×2). The combined EtOAc organic layers weredried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by preparative HPLC to give the product LC-42 (80mg, 24.9% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.28 (d, J=8.8 Hz,2H), 7.53 (d, J=8.8 Hz, 2H), 7.43-7.50 (m, 2H), 7.04 (d, J=8.8 Hz, 1H),3.82 (s, 3H), 2.51 (s, 3H), 1.36 (s, 9H). m/z 384 (M+H)⁺.

q. General Synthesis of LC-43, LC-44, and LC-45

i. Preparation ofN-(4-(tert-butyl)phenyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-amine(LC-43) (1) Synthesis of 98a

A solution of compound 96a (3.0 g, 11 mmol), DPPA (2.6 mL, 12 mmol), TEA(3.06 mL, 22 mmol) in toluene (35 mL) was stirred at room temperaturefor 6 hours. (4-Methoxy-phenyl)-methanol (3.8 g, 27.5 mmol) was thenadded and the reaction was heated to 100° C. for 18 hours. EtOAc (40 mL)was added to the reaction and the mixture was washed with aqueousNaHCO₃. The EtOAc organic layer was dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by silica gelchromatography (Petroleum Ether/EtOAc=10/1 to 2/1) to give product 98a(1.4 g, 31.8% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.28 (d, J=6.8Hz, 2H), 6.91-6.99 (m, 2H), 6.86-6.88 (m, 1H), 6.82-6.84 (m, 2H), 5.10(s, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3.67 (s, 3H), 2.10 (s, 3H). m/z 399(M+H)⁺.

(2) Synthesis of 99a

A solution of compound 98a (1.4 g, 3.5 mmol) and Phenol (493 mg, 5.25mmol) in CF₃COOH (3 mL) and DCM (15 mL) was stirred at room temperaturefor 1 hour. The reaction mixture was then concentrated with a Rotavapor.The residue was basified with aqueous NaOH and then extracted with EtOAc(15 mL×3). The combined organic layers were dried with anhydrous Na₂SO₄and concentrated with a Rotavapor to give crude product 99a (600 mg,73.2% yield). m/z 235 (M+H)⁺.

(3) Synthesis of LC-43

A suspension of compound 99a (500 mg, 2.13 mmol),1-bromo-4-tert-butyl-benzene (587 mg, 2.52 mmol), (tBu₃P)₂Pd (217 mg,0.426 mmol) and Cs₂CO₃ (1.38 g, 4.26 mmol) in dioxane (15 mL) was heatedto 110° C. for 2 hours under N₂. The reaction mixture was then filteredand concentrated with a Rotavapor. The residue was purified bypreparative HPLC to give product LC-43 (200 mg, 25.6% yield). ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 7.22 (d, J=8.8 Hz, 2H), 6.98-7.02 (m, 3H),6.72 (d, J=8.8 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.06 (s, 3H), 1.27(s, 9H). m/z 367 (M+H)⁺.

ii. Preparation ofN-(4-(tert-butyl)phenyl)-1-(2-methoxy-5-methylphenyl)-5-methyl-1H-1,2,3-triazol-4-amine(LC-44) (1) Synthesis of 98b

A solution of compound 96b (1.0 g, 4.05 mmol), DPPA (0.93 mL, 4.25mmol), TEA (1.11 mL, 8.1 mmol) in toluene (15 mL) was stirred at roomtemperature for 6 hours. (4-Methoxy-phenyl)-methanol (1.4 g, 10.125mmol) was then added and the reaction was heated to 100° C. for 18hours. EtOAc (30 mL) was added to the reaction and the mixture waswashed with aqueous NaHCO₃. The EtOAc organic layer was dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by silica gel chromatography (Petroleum Ether/EtOAc=20/1 to2/1) to give product 98b (0.5 g, 32.2% yield). m/z 383 (M+H)⁺.

(2) Synthesis of 99b

A solution of compound 98b (0.5 g, 1.3 mmol) and Phenol (190 mg, 2 mmol)in CF₃COOH (1 mL) and DCM (4 mL) was stirred at room temperature for 1hour. The reaction mixture was then concentrated with a Rotavapor. Theresidue was basified with aqueous K₂CO₃ and then extracted with DCM (10mL×2). The combined organic layers were dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor to give crude product 99b (190 mg, 66.7%yield). m/z 219 (M+H)⁺.

(3) Synthesis of LC-44

A suspension of compound 99b (190 mg, 0.87 mmol),1-bromo-4-tert-butyl-benzene (240 mg, 1.33 mmol), (tBu₃P)₂Pd (89 mg,0.174 mmol) and Cs₂CO₃ (567 mg, 1.74 mmol) in dioxane (10 mL) was heatedto 110° C. for 2 hours under N₂. The reaction mixture was then filteredand concentrated with a Rotavapor. The residue was purified bypreparative HPLC to give product LC-44 (75 mg, 23.7% yield). ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 7.24 (d, J=8.8 Hz, 1H), 7.16-7.18 (m, 3H),6.91 (d, J=8.8 Hz, 1H), 6.66 (d, J=8.8 Hz, 2H), 3.74 (s, 3H), 2.30 (s,3H), 1.99 (s, 3H), 1.23 (s, 9H). m/z 364 (M+H)⁺.

iii. Preparation ofN-(4-(tert-butyl)phenyl)-1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-amine(LC-45) (1) Synthesis of 98c

A solution of compound 96c (3.0 g, 11.2 mmol), DPPA (2.4 mL, 11.2 mmol),TEA (3.1 mL, 22.4 mmol) in toluene (35 mL) was stirred at roomtemperature for 6 hours. (4-Methoxy-phenyl)-methanol (3.86 g, 28 mmol)was then added and the reaction was heated to 100° C. for 18 hours.EtOAc (40 mL) was added to the reaction and the mixture was washed withaqueous NaHCO₃. The EtOAc organic layer was dried with anhydrous Na₂SO₄and concentrated with a Rotavapor. The residue was purified by silicagel chromatography (Petroleum Ether/EtOAc=10/1 to 2/1) to give product98c (0.4 g, 8.9% yield). m/z 403 (M+H)⁺.

(2) Synthesis of 99c

A solution of compound 98c (0.4 g, 0.99 mmol) and Phenol (140 mg, 1.49mmol) in CF₃COOH (2 mL) and DCM (10 mL) was stirred at room temperaturefor 1 hour. The reaction mixture was then concentrated with a Rotavapor.The residue was basified with aqueous NaOH and then extracted with DCM(15 mL×3). The combined organic layers were dried with anhydrous Na₂SO₄and concentrated with a Rotavapor to give crude product 99c (160 mg,68.1% yield). m/z 239 (M+H)⁺.

(3) Synthesis of LC-45

A suspension of compound 99c (160 mg, 0.67 mmol),1-bromo-4-tert-butyl-benzene (185 mg, 0.87 mmol), (tBu₃P)₂Pd (68 mg,0.134 mmol) and Cs₂CO₃ (437 mg, 1.34 mmol) in dioxane (9 mL) was heatedto 110° C. for 2 hours under N₂. The reaction mixture was then filteredand concentrated with a Rotavapor. The residue was purified bypreparative HPLC to give product LC-45 (80 mg, 32.2% yield). ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 7.45-7.49 (m, 2H), 7.22-7.26 (m, 2H), 7.03 (d,J=8.8 Hz, 1H), 6.72 (d, J=8.4 Hz, 2H), 3.83 (s, 3H), 2.07 (s, 3H), 1.28(s, 9H). m/z 371 (M+H)⁺.

r. General Synthesis of LC-46, LC-47, and LC-48

i. Preparation ofN-(4-(tert-butyl)phenyl)-1-(2,5-dimethoxyphenyl)-N,5-dimethyl-1H-1,2,3-triazol-4-amine(LC-46)

A solution of compound LC-43 (100 mg, 0.27 mmol), HCHO (100 mg, 0.27mmol, 37% in H₂O) and MgSO₄ (0.5 g) in methanol (4.2 mL) and AcOH (0.5mL) was stirred at room temperature for 2 hours. NaBH₃CN (34 mg, 0.54mmol) was then added and the mixture was stirred for another 18 hours atroom temperature. The reaction mixture was filtered. The filtrate wasconcentrated with a Rotavapor and the residue was purified bypreparative HPLC to give product LC-46 (90 mg, 88.2% yield). ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 7.24-7.26 (m, 2H), 7.00-7.08 (m, 3H), 6.69 (d,J=8.8 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.40 (s, 3H), 1.99 (s, 3H),1.27 (s, 9H). m/z 381 (M+H)⁺.

ii. Preparation ofN-(4-(tert-butyl)phenyl)-1-(2-methoxy-5-methylphenyl)-N,5-dimethyl-1H-1,2,3-triazol-4-amine(LC-47)

A solution of compound LC-44 (200 mg, 0.57 mmol), HCHO (116 mg, 1.43mmol, 37% in H₂O) and MgSO₄ (1 g) in methanol (4.9 mL) and AcOH (0.7 mL)was stirred at room temperature for 2 hours. NaBH₃CN (72 mg, 1.14 mmol)was then added and the mixture was stirred for another 18 hours at roomtemperature. The reaction mixture was filtered. The filtrate wasconcentrated with a Rotavapor and the residue was purified bypreparative HPLC to give product LC-47 (180 mg, 86.7% yield). ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 7.28 (d, J=8.8 Hz, 1H), 7.22-7.24 (m, 3H),6.97 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 2H), 3.82 (s, 3H), 3.79 (s,3H), 3.38 (s, 3H), 2.35 (s, 3H), 1.93 (s, 3H), 1.27 (s, 9H). m/z 365(M+H)⁺.

iii. Preparation ofN-(4-(tert-butyl)phenyl)-1-(5-chloro-2-methoxyphenyl)-N,5-dimethyl-1H-1,2,3-triazol-4-amine(LC-48)

A solution of compound LC-45 (100 mg, 0.27 mmol), HCHO (44 mg, 0.27mmol, 37% in H₂O) and MgSO₄ (0.5 g) in methanol (2.1 mL) and AcOH (0.3mL) was stirred at room temperature for 2 hours. NaBH₃CN (34 mg, 0.54mmol) was then added and the mixture was stirred for another 18 hours atroom temperature. The reaction mixture was filtered. The filtrate wasconcentrated with a Rotavapor and the residue was purified bypreparative HPLC to give product LC-48 (55 mg, 53.0% yield). ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 7.47-7.49 (m, 2H), 7.26-7.27 (m, 2H), 7.02 (d,J=8.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 3.82 (s, 3H), 3.85 (s, 3H), 3.40(s, 3H), 1.96 (s, 3H), 1.27 (s, 9H). m/z 385 (M+H)⁺.

s. General Synthesis of LC-70, LC-71, and LC-72

i. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(2,5-dimethoxyphenyl)-1-methyl-1H-imidazole(LC-70, 104a) (1) Synthesis of 102a

A solution of compound 101a ((1.6 g, 10 mmol), compound sodium4-(tert-butyl)benzenesulfinate (3.3 g, 15 mmol) and CuI (1.9 g, 10 mmol)in DMF (20 mL) was heated at 110° C. for 18 hours under N₂. The reactionwas then cooled down and filtered. H₂O (100 mL) was added to thefiltrate and the mixture was extracted with EtOAc (100 mL×3). Thecombined organic layers were dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by silica gelchromatography (Petroleum Ether/EtOAc=10/1 to 2/1) to give the chemical102a (1.18 g, 42% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.83 (d, 2H,J=8.4 Hz), 7.72 (s, 1H), 7.53 (d, 2H, J=8.4 Hz), 7.48 (s, 1H), 3.71 (s,3H), 1.31 (s, 9H). m/z 279 (M+H)⁺.

(2) Synthesis of 103

A solution of compound 102a (1.1 g, 4 mmol), NBS (1.06 g, 6 mmol) andAIBN (16.4 mg, 0.1 mmol) in CCl₄ (30 mL) was stirred at 60° C. for 18hours. The mixture was concentrated with a Rotavapor and the residue waspurified by preparative TLC (Petroleum Ether/EtOAc=2/1) to give compound103a (270 mg, 19% yield). m/z 357 (M+H)⁺.

(3) Synthesis of LC-70 (104a)

A solution of compound 103a (72 mg, 0.2 mmol),2,5-dimethoxyphenylboronic acid (73 mg, 0.4 mmol), Pd(dppf)Cl₂ (8 mg)and K₂CO₃ (138 mg, 1 mmol) in dioxane (3 mL) and H₂O (0.6 mL) was heatedat 90° C. for 4 hr under N₂. After the reaction was cooled down to roomtemperature, H₂O (5 mL) was added and the mixture was extracted withEtOAc (5 mL×3). The combined organic layers were dried with anhydrousNa₂SO₄ and concentrated with a Rotavapor. The residue was purified bypreparative HPLC to give compound LC-70 (104a, 30 mg, 36% yield). ¹H NMR(CDCl₃, 400 MHz): δ (ppm) 7.83-7.85 (m, 2H), 7.79 (s, 1H), 7.52-7.54 (m,2H), 6.97-7.00 (m, 1H), 6.89-6.90 (m, 1H), 6.84-6.87 (m, 1H), 3.70 (s,3H), 3.66 (s, 3H), 3.54 (s, 3H), 1.28 (s, 9H). m/z 415 (M+H)⁺.

ii. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(2-methoxy-5-methylphenyl)-1-methyl-1H-imidazole(LC-71, 104b)

The preparation of compound LC-71 (20 mg, 25% yield) was similar to thepreparation of compound LC-70 except that2-methoxy-5-methyl-phenylboronic acid was used to replace the2,5-dimethoxyphenylboronic acid in the preparation of compound LC-70. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 7.86 (d, 2H, J=8.8 Hz), 7.79 (s, 1H), 7.54(d, 2H, J=8.8 Hz), 7.19-7.24 (m, 2H), 6.83 (d, 1H, J=8.4 Hz), 3.70 (s,3H), 3.49 (s, 3H), 2.27 (s, 3H), 1.32 (s, 9H). m/z 399 (M+H)⁺.

iii. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(5-chloro-2-methoxyphenyl)-1-methyl-1H-imidazole(LC-72, 104c)

The preparation of compound LC-72 (23 mg, 27.3% yield) was similar tothe preparation of compound LC-70 except that2-methoxy-5-chloro-phenylboronic acid was used to replace the2,5-dimethoxyphenylboronic acid in the preparation of compound LC-70. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 7.82-7.85 (m, 3H), 7.55 (d, 2H, J=8.4 Hz),7.41-7.43 (m, 1H), 7.30 (d, 1H, J=2.0 Hz), 6.89 (d, 1H, J=9.2 Hz), 3.73(s, 3H), 3.57 (s, 3H), 1.29 (s, 9H). m/z 419 (M+H)⁺.

t. General Synthesis of LC-67, LC-68, and LC-69

i. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(2,5-dimethoxyphenyl)-1H-imidazole(LC-67) (1) Synthesis of 102b

A solution of compound 101b³³ (2.76 g, 10 mmol), compound sodium4-(tert-butyl)benzenesulfinate (2.2 g, 10 mmol) and CuI (1.9 g, 10 mmol)in DMF (50 mL) was heated at 110° C. for 18 hours under N₂. The reactionwas then cooled down and filtered. H₂O (100 mL) was added to thefiltrate and the mixture was extracted with EtOAc (100 mL×3). Thecombined organic layers were dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by silica gelchromatography (Petroleum Ether/EtOAc=10/1 to 2/1) to give the chemical102b (551 mg, 14% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.98 (d, 2H,J=8.4 Hz), 7.77 (s, 1H), 7.65 (s, 1H), 7.55 (d, 2H, J=8.4 Hz), 5.31 (s,2H), 3.52 (t, 2H, J=8.0 Hz), 1.34 (s, 9H), 0.92 (t, 2H, J=8.0 Hz), 0.00(s, 9H). m/z 395 (M+H)⁺.

(2) Synthesis of 103b

A solution of compound 102b (394 mg, 1 mmol), NBS (354 g, 2 mmol) andAIBN (16.4 mg, 0.1 mmol) in CCl₄ (20 mL) was stirred at 60° C. for 18hours. The mixture was concentrated with a Rotavapor and the residue waspurified by preparative TLC (Petroleum Ether/EtOAc=2/1) to give compound103b (206 mg, 44% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.96 (d, 2H,J=8.4 Hz), 7.78 (s, 1H), 7.54 (d, 2H, J=8.4 Hz), 5.28 (s, 2H), 3.56 (t,2H, J=8.0 Hz), 1.33 (s, 9H), 0.93 (t, 2H, J=8.0 Hz), 0.00 (s, 9H). m/z473 (M+H)⁺.

(3) Synthesis of 104e

A solution of compound 103b (94 mg, 0.2 mmol),2,5-dimethoxyphenylboronic acid (73 mg, 0.4 mmol), Pd(dppf)Cl₂ (8 mg)and K₂CO₃ (138 mg, 1 mmol) in dioxane (3 mL) and H₂O (0.6 mL) was heatedat 90° C. for 4 hr under N₂. After the reaction was cooled down to roomtemperature, H₂O (5 mL) was added and the mixture was extracted withEtOAc (5 mL×3). The combined organic layers were dried with anhydrousNa₂SO₄ and concentrated with a Rotavapor. The residue was purified bypreparative TLC (Petroleum Ether/EtOAc=2/1) to give compound 104e (98mg, 92% yield). m/z 531 (M+H)⁺.

(4) Synthesis of LC-67

A solution of compound 104e (98 mg, 0.184 mmol) and TBAF (500 mg) in THF(2 mL) was heated at 60° C. for 2 hours under N₂. After cooled down, thereaction was diluted with H₂O (10 mL) and extracted with EtOAc (30mL×2). The combined organic layers were dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by preparativeHPLC to yield the compound LC-67 (68 mg, 92% yield). ¹H NMR (CDCl₃, 400MHz): δ (ppm) 7.98 (d, 2H, J=8.4 Hz), 7.85 (d, 1H, J=1.6 Hz), 7.74 (s,1H), 7.49 (d, 2H, J=8.8 Hz), 6.89 (s, 2H), 3.94 (s, 3H), 3.81 (s, 3H),1.28 (s, 9H). m/z 401 (M+H)⁺.

ii. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(2-methoxy-5-methylphenyl)-1H-imidazole(LC-68)

The preparation of compound LC-68 (34 mg, 48.1% yield) was similar tothe preparation of compound LC-67 except that2-methoxy-5-methyl-phenylboronic acid was used to replace the2,5-dimethoxyphenylboronic acid in the preparation of compound LC-67. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 10.70 (s, 1H), 8.15 (s, 1H), 7.98 (d, 2H,J=8.0 Hz), 7.73 (s, 1H), 7.49 (d, 2H, J=8.4 Hz), 7.12 (d, 1H, J=7.2 Hz),6.86 (d, 1H, J=8.4 Hz), 3.95 (s, 3H), 2.30 (s, 3H), 1.28 (s, 9H). m/z385 (M+H)⁺.

iii. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(5-chloro-2-methoxyphenyl)-1H-imidazole(LC-69)

The preparation of compound LC-69 (55 mg, 74% yield) was similar to thepreparation of compound LC-67 except that2-methoxy-5-chloro-phenylboronic acid was used to replace the2,5-dimethoxyphenylboronic acid in the preparation of compound LC-67. ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 10.68 (s, 1H), 8.32 (d, 1H, J=2.4 Hz),7.98 (d, 2H, J=8.4 Hz), 7.75 (d, 1H, J=1.6 Hz), 7.50 (d, 2H, J=8.4 Hz),7.24-7.28 (m, 1H), 6.90 (d, 1H, J=8.8 Hz), 3.98 (s, 3H), 1.29 (s, 9H).m/z 405 (M+H)⁺.

u. Synthesis of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(2,5-dimethoxyphenyl)-4-methyl-1H-imidazole(LC-73)

i. Preparation of 106a and 106b

NaH (4.8 g, 0.12 mol) was added to a solution of compound 105 (8.2 g,0.1 mol) in THF (100 mL) at 0° C. The mixture was stirred at 0° C. for15 min and SEMCl (19.9 g, 0.12 mol) was added dropwise to the mixture.The reaction was stirred for another hour at 0° C. and then quenchedwith H₂O (50 mL) and extracted with EtOAc (100 mL×3). The combinedorganic layers were dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by silica gel chromatography(Petroleum Ether/EtOAc=10/1 to 1/1) to give compound 106a and 106b (17.5g, 83% yield). m/z 213 (M+H)⁺.

II. Preparation of 107a, 107b, 108a, and 108b

NBS (12 g, 67.9 mmol) in CH₃CN (100 mL) was added dropwise to compound106a and 106b (16 g, 75.5 mmol) in CH₃CN (100 mL) at 0° C. The reactionwas stirred at room temperature for 1 hour and then quenched with H₂O(200 mL) and extracted with EtOAc (100 mL×3). The combined organiclayers were dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by silica gel chromatography(Petroleum Ether/EtOAc=10/1 to DCM/MeOH=1/1) to give compound 107a, 107b(9.2 g, 42.0% yield) and 108a, 108b (1.3 g, 5.9% yield). ¹H NMR (CD₃OD,400 MHz): δ (ppm) 7.45 (s, 1H), 5.22 (s, 2H), 3.47-3.55 (m, 2H), 2.27(s, 2H), 0.91-0.96 (m, 2H), 0.02 (s, 9H). m/z 291 (M+H)⁺.

iii. Preparation of 109

A solution of compounds 107a and 107b (9.2 g, 31.7 mmol), sodium4-(tert-butyl)benzenesulfinate (9.06 g, 41.2 mmol), and CuI (6.6 g, 34.9mmol) in DMF (100 mL) was heated at 110° C. for 18 hr under N₂. Aftercooled down to room temperature, the reaction mixture was filtered andH₂O (100 mL) was added to the filtrate. The mixture was extracted withEtOAc (100 mL×3). The combined organic layers were dried with anhydrousNa₂SO₄ and concentrated with a Rotavapor. The residue was purified bysilica gel chromatography (Petroleum Ether/EtOAc=10/1 to DCM/MeOH=15/1)to give compound 109 (100 mg, 1.14% yield). m/z 279 (M+H)⁺.

iv. Preparation of 110

NBS (64 mg, 0.36 mmol) was added to compound 109 (100 mg, 0.36 mmol) inCH₃CN (3 mL) and the solution was stirred at room temperature for 17hours. H₂O (5 mL) was then added to the reaction and the mixture wasextracted with EtOAc (5 mL×3). The combined organic layers were driedwith anhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative HPLC to give compound 110 (100 mg, 78.1% yield).m/z 257 (M+H)⁺.

v. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(2,5-dimethoxyphenyl)-4-methyl-1H-imidazole(LC-73)

A solution of compound 110 (100 mg, 0.28 mmol),2,5-dimethoxyphenylboronic acid (61 mg, 0.336 mmol), Pd(dppf)Cl₂ (10 mg)and K₂CO₃ (1.38 g, 4.26 mmol) in dioxane (3 mL) and H₂O (0.6 mL) washeated at 100° C. for 6 hours under N₂. After the reaction was cooleddown to room temperature, H₂O (5 mL) was then added and the mixture wasextracted with EtOAc (5 mL×3). The combined organic layers were driedwith anhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative HPLC to give compound LC-73 (50 mg, 43.1%yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.88 (d, J=8.4 Hz, 2H), 7.76(s, 1H), 7.44 (d, J=8.4 Hz, 2H), 6.85 (s, 2H), 3.90 (s, 3H), 3.75 (s,3H), 2.55 (s, 3H), 1.24 (s, 9H). m/z 415 (M+H)⁺.

v. Synthesis of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(5-chloro-2-methoxyphenyl)-4-methyl-1H-imidazole(LC-75)

i. Preparation of 111a and 111b

A solution of compound 108a, 108b (1 g, 3.45 mmol),2-methoxy-5-chlorophenylboronic acid (770 mg, 4.14 mmol), Pd(dppf)Cl₂(100 mg) and K₂CO₃ (0.95 g, 6.9 mmol) in dioxane (10 mL) and H₂O (2 mL)was heated at 110° C. for 6 hours under N₂. After cooled down to theroom temperature, the reaction mixture was added with H₂O (10 mL) andextracted with EtOAc (10 mL×3). The combined organic layers were driedwith anhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative HPLC to give compound 111a and 111b (300 mg, 25%yield). m/z 353 (M+H)⁺.

ii. Preparation of 112a and 112b

NBS (151 mg, 0.85 mmol) was added to a solution of 111a and 111b (300mg, 0.85 mmol) in CH₃CN (5 mL) at −30° C. The reaction was then stirredat room temperature for 0.5 hour. The reaction was quenched with H₂O (5mL) and the mixture was extracted with EtOAc (10 mL×3). The combinedorganic layers were dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by preparative HPLC to give compound112a and 112b (260 mg, 85.6% yield). m/z 358 (M+H)⁺.

iii. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(5-chloro-2-methoxyphenyl)-4-methyl-1H-imidazole(LC-75)

A solution of compound 112a, 112b (260 mg, 0.73 mmol), sodium4-(tert-butyl)benzenesulfinate (208 mg, 0.94 mmol), and CuI (153 mg, 0.8mmol) in DMF (5 mL) was heated at 110° C. for 18 hr under N₂. Aftercooled down to the room temperature, the reaction was quenched with H₂O(10 mL) and extracted with EtOAc (10 mL×3). The combined organic layerswere dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by preparative HPLC to give compound LC-75 (15 mg,4.9% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 10.21 (s, 1H), 8.24 (s,1H), 7.91 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.17 (s, 1H), 6.83(d, J=8.4 Hz, 1H), 3.90 (s, 3H), 2.60 (s, 3H), 1.24 (s, 9H). m/z 419(M+H)⁺.

w. Synthesis of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(2-methoxy-5-methylphenyl)-4-methyl-1H-imidazole(LC-74)

i. Preparation of 114

NaH (200 mg, 5 mmol) was added to a stirred solution of compound 113(952 mg, 4 mmol) in THF (10 mL) at 0° C. and the reaction was stirred at0° C. for 15 min. SEMCl (797 mg, 4.8 mmol) was added and the reactionwas stirred for another hour at 0° C. The reaction was then quenchedwith H₂O (30 mL) and extracted with EtOAc (30 mL×3). The combinedorganic layers were dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by silica gel chromatography(Petroleum Ether/EtOAc=10/1 to 1/1) to give compound 114 (1.2 g, 82%yield). m/z 369 (M+H)⁺.

ii. Preparation of 115

A solution of compound 114 (1.2 g, 3.3 mmol),2-methoxy5-methyl-phenylboronic acid (664 mg, 4 mmol), Pd(dppf)Cl₂ (81.6mg, 0.1 mmol) and K₂CO₃ (1.38 g, 10 mmol) in dioxane (15 mL) and H₂O (5mL) was heated at 100° C. for 3 hr under N₂. After cooled down to roomtemperature, the reaction was quenched with H₂O (30 mL) and extractedwith EtOAc (50 mL×2). The combined organic layers were dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative TLC (Petroleum Ether/EtOAc=5/1) to give compound115 (450 mg, 33% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.37 (s, 1H),7.32 (d, 1H, J=8.4 Hz), 6.95 (d, 1H, J=8.4 Hz), 5.23 (s, 2H), 3.86 (s,3H), 3.21 (t, 2H, J=8.4 Hz), 2.39 (s, 3H), 2.41 (s, 3H), 0.79 (t, 2H,J=8.4 Hz), 0.00 (s, 9H). m/z 411 (M+H)⁺.

iii. Preparation of 116

A solution of compound 115 (410 mg, 1 mmol), sodium4-(tert-butyl)benzenesulfinate (440 mg, 2 mmol), and CuI (190 mg, 1mmol) in DMF (10 mL) was heated at 110° C. for 18 hours under N₂. Aftercooled down to room temperature, the reaction was filtered. The filtratewas added with H₂O (20 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by preparativeTLC (Petroleum Ether/EtOAc=2/1) to give compound 116 (25 mg, 5% yield).m/z 529 (M+H)⁺.

iv. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(2-methoxy-5-methylphenyl)-4-methyl-1H-imidazole(LC-74)

A solution of compound 116 (25 mg, 0.05 mmol) and TBAF (500 mg) in THF(2 mL) was heated at 60° C. for 2 hours under N₂. After cooled down tothe room temperature, the reaction was quenched with H₂O (10 mL) andextracted with EtOAc (30 mL×2). The combined organic layers were driedwith anhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative HPLC to give compound LC-74 (11 mg, 55% yield).¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.04 (s, 1H), 7.90 (d, 2H, J=8.4 Hz),7.53 (d, 2H, J=8.8 Hz), 7.22 (s, 1H), 6.91 (d, 1H, J=8.8 Hz), 4.01 (s,3H), 2.58 (s, 3H), 2.29 (s, 3H), 1.30 (s, 9H). m/z 399 (M+H)⁺.

x. General Synthesis of LC-76, LC-77, and LC-78

i. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(2,5-dimethoxyphenyl)-1,4-dimethyl-1H-imidazole(LC-76) (1) Synthesis of 118a

A solution of compound 117 (1.0 g, 3.97 mmol),2,5-dimethoxyphenylboronic acid (722 mg, 3.97 mmol), Pd(dppf)Cl₂ (100mg) and K₂CO₃ (1.1 g, 7.94 mmol) in dioxane (10 mL) and H₂O (2 mL) washeated at 100° C. for 3 hours under N₂. After cooled down to roomtemperature, the reaction was quenched with H₂O (15 mL) and extractedwith EtOAc (15 mL×3). The combined organic layers were dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative TLC (Petroleum Ether/EtOAc=2/1) to give compound118a (500 mg, 40.6% yield). m/z 311 (M+H)⁺.

(2) Synthesis of LC-76

A solution of compound 118a (500 mg, 1.6 mmol), sodium4-(tert-butyl)benzenesulfinate (704 mg, 3.2 mmol), and CuI (337 mg, 1.77mmol) in DMF (6 mL) was heated at 110° C. for 18 hours under N₂. Thereaction was cooled down to room temperature and filtered. The filtratewas added with H₂O (10 mL) and extracted with EtOAc (10 mL×3). Thecombined organic layers were dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by preparativeHPLC to give compound LC-76 (100 mg, 14.6% yield). ¹H NMR (CDCl₃, 400MHz): δ (ppm) 7.85 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 6.93-7.13(m, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 3.65 (s, 3H), 2.75 (s, 3H), 1.34(s, 9H). m/z 429 (M+H)⁺.

ii. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(2-methoxy-5-methylphenyl)-1,4-dimethyl-1H-imidazole(LC-77) (1) Synthesis of 118b

A solution of compound 117 (1.0 g, 3.97 mmol),2-methoxy-5-methyl-phenylboronic acid (659 mg, 3.97 mmol), Pd(dppf)Cl₂(100 mg) and K₂CO₃ (1.1 g, 7.94 mmol) in dioxane (10 mL) and H₂O (2 mL)was heated at 100° C. for 3 hours under N₂. After cooled down to roomtemperature, the reaction was quenched with H₂O (15 mL) and extractedwith EtOAc (15 mL×3). The combined organic layers were dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative TLC (Petroleum Ether/EtOAc=2/1) to give compound118b (400 mg, 34.2% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.23-7.24(m, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 3.77 (s, 3H),3.38 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H). m/z 295 (M+H)⁺.

(2) Synthesis of LC-77

A solution of compound 118b (400 mg, 1.36 mmol), sodium4-(tert-butyl)benzenesulfinate (598 mg, 2.72 mmol), and CuI (284 mg, 1.5mmol) in DMF (6 mL) was heated at 110° C. for 18 hours under N₂. Thereaction was cooled down to room temperature and filtered. The filtratewas added with H₂O (10 mL) and extracted with EtOAc (10 mL×3). Thecombined organic layers were dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by preparativeHPLC to give compound LC-77 (80 mg, 14.3% yield). ¹H NMR (CDCl₃, 400MHz): δ (ppm) 7.80 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.30 (d,J=8.8 Hz, 1H), 7.19 (s, 1H), 6.84 (d, J=8.8 Hz, 1H), 3.71 (s, 3H), 3.60(s, 3H), 2.70 (s, 3H), 2.22 (s, 3H), 1.29 (s, 9H). m/z 413 (M+H)⁺.

iii. Preparation of5-((4-(tert-butyl)phenyl)sulfonyl)-2-(5-chloro-2-methoxyphenyl)-1,4-dimethyl-1H-imidazole(LC-78) (1) Synthesis of 118c

A solution of compound 117 (1.0 g, 3.97 mmol),2-methoxy-5-chloro-phenylboronic acid (738 mg, 3.97 mmol), Pd(dppf)Cl₂(100 mg) and K₂CO₃ (1.1 g, 7.94 mmol) in dioxane (10 mL) and H₂O (2 mL)was heated at 100° C. for 3 hours under N₂. After cooled down to roomtemperature, the reaction was quenched with H₂O (15 mL) and extractedwith EtOAc (15 mL×3). The combined organic layers were dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative TLC (Petroleum Ether/EtOAc=2/1) to give compound118c (500 mg, 40.0% yield). m/z 315 (M+H)⁺.

(2) Synthesis of LC-78

A solution of compound 118c (500 mg, 1.6 mmol), sodium4-(tert-butyl)benzenesulfinate (704 mg, 3.2 mmol), and CuI (337 mg, 1.77mmol) in DMF (6 mL) was heated at 110° C. for 18 hours under N₂. Thereaction was cooled down to room temperature and filtered. The filtratewas added with H₂O (10 mL) and extracted with EtOAc (10 mL×3). Thecombined organic layers were dried with anhydrous Na₂SO₄ andconcentrated with a Rotavapor. The residue was purified by preparativeHPLC to give compound LC-78 (150 mg, 21.7% yield). ¹H NMR (CDCl₃, 400MHz): δ (ppm) 7.85 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.49 (d,J=8.8 Hz, 1H), 7.38 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 3.63(s, 3H), 2.72 (s, 3H), 1.34 (s, 9H). m/z 433 (M+H)⁺.

y. General Synthesis of LC-79, LC-80, and LC-81

i. Preparation of 120

A solution of compound 119 (605 mg, 2.5 mmol), NBS (442 g, 2.5 mmol) andAIBN (16.4 mg, 0.1 mmol) in CCl₄ (20 mL) was stirred at 60° C. for 18hours. The mixture was concentrated with a Rotavapor and the residue waspurified by preparative TLC (Petroleum Ether/EtOAc=5/1) to give product120 (488 mg, 61% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.18-8.20 (m,2H), 7.47-4.49 (m, 2H), 7.06 (s, 1H), 4.02 (s, 3H), 1.32 (s, 9H). m/z321 (M+H)⁺.

ii. Preparation of(4-(tert-butyl)phenyl)(2-(2,5-dimethoxyphenyl)-1-methyl-1H-imidazol-5-yl)methanone(LC-79)

A solution of compound 120 (160 mg, 0.5 mmol),2,5-dimethoxyphenylboronic acid (182 mg, 1 mmol), Pd(dppf)Cl₂ (16 mg)and K₂CO₃ (276 mg, 2 mmol) in dioxane (5 mL) and H₂O (1 mL) was heatedat 100° C. for 3 hours under N₂. H₂O (5 mL) was then added and themixture was extracted with EtOAc (15 mL×3). The combined organic layerswere dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by preparative HPLC to give the product LC-79 (108mg, 57% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.03 (d, 2H, J=8.0 Hz),7.51 (d, 2H, J=8.4 Hz), 7.32 (s, 1H), 7.00-7.03 (m, 1H), 6.95 (d, 1H,J=8.8 Hz), 6.85 (d, 1H, J=2.8 Hz), 3.83 (s, 3H), 3.79 (d, 6H, J=3.6 Hz),1.33 (s, 9H). m/z 379 (M+H)⁺.

iii. Preparation of(4-(tert-butyl)phenyl)(2-(2-methoxy-5-methylphenyl)-1-methyl-1h-imidazol-5-yl)methanone (LC-80)

The preparation of compound LC-80 (56 mg, 30.9% yield) was similar tothe preparation of compound LC-79 except that2-methoxy-5-methyl-phenylboronic acid was used as the starting materialto replace the 2,5-dimethoxyphenylboronic acid in the preparation ofcompound LC-79. ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.13 (d, 2H, J=8.4 Hz),7.43 (d, 2H, J=8.4 Hz), 7.14-7.18 (m, 2H), 7.03 (d, 1H, J=1.2 Hz), 6.83(d, 1H, J=8.4 Hz), 3.76 (s, 3H), 3.73 (s, 3H), 2.26 (s, 3H), 1.28 (s,9H). m/z 363 (M+H)⁺.

iv. Preparation of(4-(tert-butyl)phenyl)(2-(5-chloro-2-methoxyphenyl)-1-methyl-1H-imidazol-5-yl)methanone(LC-81)

The preparation of compound LC-81 (77 mg, 40.3% yield) was similar tothe preparation of compound LC-79 except that2-methoxy-5-chloro-phenylboronic acid was used as the starting materialto replace the 2,5-dimethoxyphenylboronic acid in the preparation ofcompound LC-79. ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.99 (d, 2H, J=8.4 Hz),7.51 (d, 2H, J=8.0 Hz), 7.44-7.46 (m, 1H), 7.35 (s, 1H), 7.30 (d, 1H,J=2.4 Hz), 6.96 (d, 1H, J=9.2 Hz), 3.84 (s, 3H), 3.82 (s, 3H), 1.33 (s,9H). m/z 383 (M+H)⁺.

z. Synthesis of2-(tert-butyl)-5-((1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)phenol(LC-88)

i. Preparation of 122

Sodium hydride (60% in mineral oil, 6.2 g, 0.155 mol) was added inportions to a solution of compound 121 (42.8 g, 0.15 mol) in DMF (250mL) at 0° C. The reaction was stirred at 0° C. for 30 min. Benzylbromide (26.5 g, 0.155 mol) was then added dropwise and the mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto water, and the aqueous layer was extracted with ethyl acetatetwice. The combined organic layers were washed with brine, dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by silica gel chromatography (Petroleum Ether/EtOAc=10/1) togive compound 122 (15 g, 39.5% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm)7.78-7.75 (m, 2H), 7.48-7.33 (m, 6H), 5.18 (s, 2H), 1.40 (s, 9H).

ii. Preparation of 123

NH₄Cl (21.4 g, 0.33 mol), followed by Zn dust (15 g, 0.38 mol) inportions was added to a solution of compound 122 (10.5 g, 0.037 mol) inMeOH (150 mL) and THF (150 mL) at room temperature. The reaction wasstirred at room temperature overnight. The mixture was filtered and thefiltrate was concentrated with a Rotavapor. The residue was purified bysilica gel chromatography (Petroleum Ether/EtOAc=10/1 to 5/1) to givecompound 123 (7 g, 74% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm)7.45-7.26 (m, 5H), 7.09 (d, J=8.0 Hz, 1H), 6.32 (d, J=1.6 Hz, 1H), 6.28(dd, J=8.0 Hz, 1.6 Hz, 1H), 5.07 (s, 2H), 3.55 (brs, 2H), 1.36 (s, 9H).m/z 256 (M+H)⁺.

iii. Preparation of 124

HOAc (12.5 mL) and then concentrated HCl (12.5 mL) were added to asolution of compound 123 (5.1 g, 0.02 mol) in acetonitrile (120 mL) at−5° C. The mixture was stirred at −5° C. for 30 min and a solution ofsodium nitrite (1.63 g, 0.024 mol) in water (2.5 mL) was added dropwisein 10 minutes at −5° C. The reaction was stirred at −5° C. for 30minutes and then cooled down to −20° C. The reaction was bubbled intoSO₂ gas for 10 minutes, followed by the addition of a solution ofCuCl₂-2H₂O (3.8 g, 0.022 mol) in water (3.5 mL) in one portion. Thereaction was then stirred at room temperature overnight. The reactionmixture was quenched with water and then extracted with ethyl acetate(150 mL×3). The combined organic layers were dried with anhydrous Na₂SO₄and concentrated with a Rotavapor. The residue was purified by silicagel chromatography (Petroleum Ether/EtOAc=10/1) to give compound 124(3.3 g, 50% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.60-7.34 (m, 8H),5.18 (s, 2H), 1.40 (s, 9H).

iv. Preparation of 125

A solution of compound 124 (3.3 g, 0.01 mol), Na₂SO₃ (1.51 g, 0.012 mol)and NaHCO₃ (1.68 g, 0.02 mol) in water (40 mL) was heated at 80° C. for3 hours. Water was removed with a Rotavapor and the residual water wasfurther removed with toluene by azeotropic distillation to give crudecompound 125 which was used directly for the next step without furtherpurification.

v. Preparation of 126

A solution of compound 125 (3.26 g, 0.01 mol) and chloroacetone (5.0 g,0.05 mol) in DMF (40 mL) was stirred at room temperature overnight. Thereaction mixture was poured into water and extracted with ethyl acetatethree times. The organic layer was washed with brine, dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor to give compound 126which was used directly for the next step without further purification.

vi. Preparation of 127

BBr₃ (0.5 mL) was added to a solution of crude compound 126 in DCM (20mL) at room temperature and the reaction was stirred at room temperaturefor 4 hours. The reaction was quenched with saturated NaHCO₃ aqueoussolution and the mixture was extracted with DCM three times. Thecombined organic layer was washed with brine, dried with anhydrousNa₂SO₄ and concentrated with a Rotavapor. The residue was purified bysilica gel chromatography (Petroleum Ether/EtOAc=10/1 to 4/1) to givecompound 127 (720 mg, 26.7% yield for three steps). ¹H NMR (CDCl₃, 400MHz): δ (ppm) 7.45 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.1 Hz, 1.8 Hz, 1H),7.27 (d, J=2.1 Hz, 1H), 6.39 (s, 1H), 4.17 (s, 2H), 2.39 (s, 3H), 1.40(s, 9H). m/z 292.8 (M+Na)⁺.

vii. Preparation of2-(tert-butyl)-5-((1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)phenol(LC-88)

A solution of compound 127 (720 mg, 2.67 mmol),2-azido-1,4-dimethoxybenzene³² (573 mg, 3.2 mmol) and NaOCH₃ (288 mg,5.33 mmol) in CH₃OH (10 mL) was heated at reflux overnight. The reactionwas cooled down to room temperature, quenched with H₂O (80 mL) andextracted with EtOAc (50 mL×3). The combined EtOAc solution was washedwith brined, dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by silica gel chromatography(Petroleum Ether/EtOAc=85/15 to 70/30) to give compound LC-88 (450 mg,39% yield). ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 10.34 (brs, 1H),7.47-7.21 (m, 6H), 3.74 (s, 3H), 3.73 (s, 3H), 2.36 (s, 3H), 1.35 (s,9H). m/z 432.2 (M+H)⁺.

aa. Synthesis of2-(4-((4-(tert-butyl)-3-hydroxyphenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-4-methoxyphenol(LC-83)

BBr₃ (115 mg, 0.46 mmol) was added to a solution of compound LC-88 (100mg, 0.23 mmol) in anhydrous DCM (5 mL) at 0° C. and the reaction wasstirred at this temperature for 5 min. The reaction mixture was quenchedwith saturated NaHCO₃ aqueous solution (20 mL) and extracted with DCM(30 mL×3). The combined organic layer was washed with brine, dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative HPLC to give compound LC-83 (46 mg, 47% yield).¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 10.33 (brs, 1H), 10.07 (brs, 1H),7.45-7.35 (m, 3H), 7.06-7.00 (m, 3H), 3.68 (s, 3H), 2.37 (s, 3H), 1.33(s, 9H). m/z 418.2 (M+H)⁺.

bb. Synthesis of2-(tert-butyl)-5-((1-(5-hydroxy-2-methoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)phenol(LC-82)

i. Preparation of 128

BBr₃ (783 mg, 3.1 mmol) was added to a solution of compound LC-88 (270mg, 0.63 mmol) in anhydrous DCM (10 mL) at 0° C. and the reaction wasthen stirred at room temperature for 2 hour. The reaction mixture wasquenched with saturated NaHCO₃ aqueous solution (20 mL) and extractedwith DCM (30 mL×3). The combined organic layer was washed with brine,dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by silica gel chromatography (PetroleumEther/EtOAc=9/1 to 3/1) to give compound 128 (180 mg, 71% yield). ¹H NMR(DMSO-d₆, 400 MHz): δ (ppm) 10.30 (s, 1H), 9.77 (s, 1H), 9.35 (s, 1H),7.44-7.34 (m, 3H), 6.92-6.85 (m, 2H), 6.73 (d, J=2.8 Hz, 1H), 2.36 (s,3H), 1.33 (s, 9H). m/z 404.0 (M+H)⁺.

ii. Preparation of2-(tert-butyl)-5-((1-(5-hydroxy-2-methoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)phenol(LC-82)

Trimethylsilyl)diazomethane (2M/L in hexane, 3 mL) was added to asolution of compound 128 (180 mg, 0.45 mmol), potassium carbonate (200mg, 1.45 mmol) in DCM (10 mL) and acetonitrile (10 mL) at roomtemperature and the reaction was stirred at this temperature for 2hours. The reaction was quenched with H₂O (20 mL) and then extractedwith EtOAc (30 mL×3). The combined organic layer was washed with brine,dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by preparative HPLC to give compound LC-82 (44 mg,23.7% yield). ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 10.31 (brs, 1H), 9.61(brs, 1H), 7.56 (m, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.15 (d, J=9.2 Hz, 1H),7.02 (dd, J=9.2 Hz, 2.8 Hz, 1H), 6.85 (J=2.8 Hz, 1H), 3.61 (s, 3H), 2.36(s, 3H), 1.33 (s, 9H). m/z 418.2 (M+H)⁺.

cc. Synthesis of5-(tert-butyl)-2-((1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)phenol(LC-84)

i. Preparation of 130

A solution of compound 129 (600 mg, 2.28 mmol), Na₂SO₃ (345 mg, 2.74mmol) and NaHCO₃ (383 mg, 4.56 mmol) in H₂O (8 mL) was heated at 80° C.for 3 hours. The reaction was cooled down to room temperature. Water inthe reaction mixture was removed with a Rotavapor and the residual waterwas further removed with toluene by azeotropic distillation to givecrude compound 130 which was used directly for the next step withoutfurther purification.

ii. Preparation of 131

A solution of compound 130 (crude, from the above step) andchloroacetone (1.3 g, 14 mmol) in DMF (20 mL) was stirred at roomtemperature overnight. The reaction was quenched with H₂O (50 mL) andextracted with EtOAC (60 mL×3). The combined organic layer was washedwith brine, dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by silica gel chromatography(Petroleum Ether/EtOAc=4/0 to 4/1) to give compound 131 (350 mg, 56.7%yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.81 (d, J=8.4 Hz, 1H), 7.11(dd, J=8.1 Hz, 1.5 Hz, 1H), 7.01 (d, J=1.2 Hz, 1H), 4.34 (s, 2H), 3.97(s, 3H), 2.38 (s, 3H), 1.32 (s, 9H).

iii. Preparation of 132

BBr₃ (0.3 mL) was added to a solution of compound 131 (330 mg, 1.16mmol) in anhydrous DCM (5 mL) at room temperature and the reaction wasthen stirred at this temperature for 4 hours. The reaction mixture wasquenched with saturated NaHCO₃ aqueous solution (20 mL) and extractedwith DCM (30 mL×3). The combined organic layer was washed with brine,dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by silica gel chromatography (PetroleumEther/EtOAc=9/1 to 3/1) to give compound 132 (180 mg, 57.5% yield). ¹HNMR (CDCl₃, 400 MHz): δ (ppm) 8.62 (brs, 1H), 7.54 (dd, J=8.1 Hz, 0.9 Hz1H), 7.06-7.01 (m, 2H), 4.20 (s, 2H), 2.38 (s, 3H), 1.29 (s, 9H).

iv. Preparation of5-(tert-butyl)-2-((1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)phenol(LC-84)

A solution of compound 132 (180 mg, 0.67 mmol),2-azido-1,4-dimethoxybenzene³² (143 mg, 0.8 mmol) and NaOCH₃ (108 mg,2.0 mmol) in CH₃OH (4 mL) was heated at reflux overnight. The reactionwas cooled down to room temperature, quenched with H₂O (30 mL) andextracted with EtOAc (20 mL×3). The combined EtOAc solution was washedwith brined, dried with anhydrous Na₂SO₄ and concentrated with aRotavapor. The residue was purified by silica gel chromatography(Petroleum Ether/EtOAc=85/15 to 70/30) to give compound LC-84 (80 mg,27.7% yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 9.05 (s, 1H), 10.07 (brs,1H), 7.78 (d, J=8.4 Hz, 1H), 7.10-7.00 (m, 4H), 6.89 (d, J=6.8 Hz, 1H),3.78 (s, 3H), 3.75 (s, 3H), 2.45 (s, 3H), 1.30 (s, 9H). m/z 432.2(M+H)⁺.

dd. Synthesis of2-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)benzene-1,4-diol(LC-85)

i. Preparation of4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole(LC-1; 134)

A solution of compound 133 (1.0 g, 3.94 mmol),2-azido-1,4-dimethoxybenzene³² (540 mg, 3.0 mmol) and NaOCH₃ (810 mg, 15mmol) in CH₃OH (10 mL) was heated at reflux overnight. The reaction wascooled down to room temperature, quenched with H₂O (30 mL) and extractedwith EtOAc (20 mL×3). The combined EtOAc solution was washed withbrined, dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor.The residue was purified by silica gel chromatography (PetroleumEther/EtOAc=85/15 to 70/30) to give compound 134 (LC-1, 380 mg, 30%yield). ¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.06 (d, J=8.8 Hz, 2H), 7.58(d, J=8.4 Hz, 2H), 7.09 (dd, J=9.2 Hz, 2.8 Hz, 1H), 7.02 (d, J=9.2 Hz,1H), 6.88 (d, J=2.8 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 2.46 (s, 3H),1.56 (s, 9H). m/z 416.1 (M+H)⁺.

ii. Preparation of2-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)benzene-1,4-diol(LC-85)

BBr₃ (500 mg, 2 mmol) was added to a solution of compound 134 (400 mg,0.96 mmol) in anhydrous DCM (10 mL) at room temperature and the reactionwas then stirred at this temperature for 2 hours. The reaction mixturewas quenched with saturated NaHCO₃ aqueous solution (20 mL) andextracted with DCM (30 mL×3). The combined organic layer was washed withbrine, dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor.The residue was purified by silica gel chromatography (PetroleumEther/EtOAc=9/1 to 3/1) to give compound LC-85 (330 mg, 88% yield). ¹HNMR (DMSO-d₆, 400 MHz): δ (ppm) 9.76 (brs, 1H), 9.34 (brs, 1H), 7.94 (d,J=8.0 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 6.92 (m, 2H), 6.73 (d, J=2.4 Hz,1H), 2.38 (s, 3H), 1.30 (s, 9H). m/z 388.2 (M+H)⁺.

ee. Synthesis of2-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-4-methoxyphenol(LC-86)

BBr₃ (225 mg, 0.9 mmol) was added to a solution of compound 134 (150 mg,0.36 mmol) in anhydrous DCM (3 mL) at 0° C. and the reaction was thenstirred at this temperature for 15 minutes. The reaction mixture wasquenched with saturated NaHCO₃ aqueous solution (10 mL) and extractedwith DCM (20 mL×3). The combined organic layer was washed with brine,dried with anhydrous Na₂SO₄ and concentrated with a Rotavapor. Theresidue was purified by preparative HPLC to give compound LC-86 (85 mg,58.6% yield). ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 8.01 (d, J=8.4 Hz, 2H),7.57 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.0 Hz, 1H), 6.98 (dd, J=8.0 Hz, 3.2Hz, 1H), 6.76 (d, J=3.2 Hz, 1H), 6.75 (brs, 1H), 3.75 (s, 3H), 2.55 (s,3H), 1.32 (s, 9H). m/z 402.1 (M+H)⁺.

ff. Synthesis of3-(4-((4-(tert-butyl)phenyl)sulfonyl)-5-methyl-1H-1,2,3-triazol-1-yl)-4-methoxyphenol(LC-87)

(Trimethylsilyl)diazomethane (1.5 mL, 2M/L in hexane) was added to asolution of compound LC-85 (150 mg, 0.39 mmol), potassium carbonate (200mg, 1.45 mmol) in DCM (5 mL) and acetonitrile (5 mL) at roomtemperature. The reaction was stirred at this temperature overnight. Thereaction was quenched with H₂O (20 mL) and extracted with EtOAc (30mL×3). The combined organic layer was washed with brine, dried withanhydrous Na₂SO₄ and concentrated with a Rotavapor. The residue waspurified by preparative HPLC to give compound LC-87 (35 mg, 24% yield).¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 9.56 (brs, 1H), 8.12 (d, J=8.4 Hz,2H), 7.75 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.8 Hz, 1H), 7.15 (d, J=8.4 Hz,1H), 7.02 (s, 1H), 3.67 (s, 3H), 2.35 (s, 3H), 1.32 (s, 9H). m/z 402.1(M+H)⁺.

3. Biology Experimentals

a. Materials and Methods

PXR binding assay kits, GeneBLAzer panel nuclear receptor cells, DMEM,phenol red-free DMEM, non-essential amino acids, sodium pyruvate, HEPES,hygromycin B, zeocin, penicillin and streptomycin were purchased fromInvitrogen (Carlsbad, Calif.) (now ThermoFisher). Tissue culture flasks,384-well low volume solid black plates, tissue culture-treated 384-wellblack clear bottom plates and tissue culture-treatedpoly-D-lysine-coated 384-well black clear bottom plates were purchasedfrom Corning Life Sciences (Tewksbury Mass.). Tissue culture-treated384-well white solid bottom plates and Steadylite HTS reagent werepurchased from PerkinElmer Life Sciences (Hopkinton, Mass.). CellTiterGlo luminescent cell viability assay reagent was obtained from Promega(Madison, Wis.). FBS and charcoal/dextran-treated FBS were purchasedfrom Hyclone (Logan, Utah). HepG2 cells were obtained from ATCC(Manassas, Va.). FuGENE 6 was purchased from Roche (Indianapolis, Ind.).DMSO, SR12813, rifampicin, la, 25-dihydroxyvitamin D3, dexamethasone,mifepristone, 9-cis-retinoic acid, GW4604, T0901317 and GW9662 werepurchased from Sigma (St. Louis, Mo.). Staurosporine was purchased fromLC Labs (Woburn, Mass.). Matrical Gel was purchased from BD (FranklinLakes, N.J.).

b. PXR Binding Assay

The time-resolved fluorescence resonance transfer (TR-FRET) hPXRcompetitive binding assay was performed according to the manufacturer'sinstructions (Invitrogen) with minor modifications. Briefly, the bindingassays were performed in 384-well low volume (20 μl per well) solidblack plates with 5 nM GST-hPXR ligand-binding domain, 40 nMfluorescent-labeled hPXR ligand (Fluormore PXR Green, also referred toas a “tracer”), 5 nM terbium-labeled anti-GST antibody, and testcompound at a variety of concentrations. DMSO (0.4%) was used as thenegative control (0% inhibition) and a potent hPXR agonist, SR-12813 at10 μM (with 0.4% DMSO) was used as the positive control (100%inhibition). The activities of individual chemicals tested at variousconcentrations (1-to-2 series dilutions for 16 concentration levels from40 μM with 0.4% final DMSO concentration) were normalized to positiveand negative controls to generate % Inhibition (PMID: 18784074).

In the reaction mixture, GST-hPXR forms a complex with theterbium-labeled anti-GST antibody and the tracer. Excitation of terbium(the donor) using a 340-nm excitation filter results in energy transferto the fluorophore of the tracer. This energy transfer is detected by anincrease in the fluorescence emission of the tracer at 520 nm and adecrease in the fluorescence emission of terbium at 495 nm. The FRETratio was calculated by dividing the emission signal at 520 nm by theemission signal at 495 nm. A competitor compound such as SR-12813replaces the tracer from the complex and decreases the FRET ratioaccordingly. The reactions were incubated at 25° C. for 30 min beforemeasuring the fluorescent emission of each well at 495 and 520 nm usinga 340-nm excitation filter, 100-μs delay time, and 200-μs integrationtime, with a PHERAStar plate reader (BMG Labtech, Durham, N.C.). Thecurve-fitting software GraphPad Prism 4.0 (Graphpad Software, La Jolla,Calif.) was used to generate the dose response curves and determine theIC₅₀ values for individually tested compounds if applicable. SR-12813has an IC₅₀ of 65 nM in this assay.

c. hPXR Tranxactivation Assays

The hPXR transactivation assays (PXR agonistic and antagonistic assays)were performed in the HepG2 cells stably expressing FLAG-hPXR andCYP3A4-luciferase reporter. Briefly, various concentrations (1-to-3series dilutions for 10 concentration levels from 40 μM with 0.5% finalDMSO concentration) of hPXR agonist rifampicin, various concentrationsof tested chemicals alone or combined with 5 μM of rifampicin, wereadded to the wells of white 384-well tissue culture-treated plates with5,000 cells in 25 μl of phenol red-free DMEM supplemented with 5%charcoal/dextran-treated FBS and incubated for 24 h at 37° C. beforeluciferase assay using Steadylite HTS (PerkinElmer Life Sciences). Theluminescence signal was detected using an Envision plate reader(PerkinElmer Life Sciences). In the agonistic assays, DMSO (0.5% finalconcentration) was used as the negative control (0% activation) andrifampicin (10 μM in 0.5% DMSO) was used as the positive control (100%activation). In the antagonistic assays, rifampicin (5 μM with 0.5%final DMSO concentration) was used as the negative control (0%inhibition) and DMSO (0.5%) was used as the positive control (100%inhibition). The activities of individual chemicals tested at variousconcentrations were normalized to the corresponding positive andnegative controls to generate % Activation in agonistic assays and %Inhibition in antagonistic assays. The curve-fitting software GraphPadPrism 4.0 (Graphpad Software, La Jolla, Calif.) was used to generate thedose response curves and determine the IC₅₀ (for hPXR antagonists) orEC₅₀ (for hPXR agonists) values for individually tested compounds ifapplicable. Rifampicin has an IC₅₀ of 1.18 μM in this assay.

d. HepG2 Cytotoxicity Assays

In the HepG2 cytotoxicity assays, various concentrations (1-to-3 seriesdilutions for 10 concentration levels from 40 μM in 0.5% final DMSOconcentration) of testing compounds, staurosporine (1-to-3 seriesdilutions for 16 concentration levels from 56 μM with 0.5% final DMSOconcentration, or 56 μM with 0.5% final DMSO concentration) or DMSO(0.5%) were added to the wells of white 384-well tissue culture-treatedplates with 2,500 cells in 25 μl of phenol red-free DMEM supplementedwith 10% FBS and incubated for 72 h at 37° C. before performing thecytotoxic assay with CellTiter Glo luminescent cell viability assay(Promega, Madison, Wis.). The luminescence signal was detected using anEnvision plate reader (PerkinElmer Life Sciences). In the cytotoxicassay, DMSO (0.5%) was used as the negative control (0% Inhibition) andstaurosporine (56 μM with 0.5% DMSO) was used as the positive control(100% Inhibition). The activities of individual chemicals tested atvarious concentrations were normalized to the positive and negativecontrols to generate % Inhibition. The curve-fitting software GraphPadPrism 4.0 (Graphpad Software, La Jolla, Calif.) was used to generate thedose response curves and determine the IC₅₀ values for individuallytested compounds if applicable. Staurosporine has an IC₅₀ of 96 nM inthis assay.

e. hCAR Transactivation Assays

In the hCAR transactivation assays, 5 million HepG2 cells were seededinto a T25 flask 24 h before transiently transfected with aplasmid:FuGENE 6 mixture (0.75 μg of pcDNA3-FLAG-hCAR, 2.25 μg ofCYP2B6-2.2 kb, and 0.3 μg of pRL-TK). 24 h post-transfection, 5,000cells in 25 μl of phenol red-free DMEM supplemented with 5%charcoal/dextran-treated FBS were seeded into each well of 384-wellwhite culture plates and treated with compounds for another 24 h priorto Dual-Glo luciferase assay, using an Envision plate reader. Relativeluciferase activity was determined by normalizing the firefly luciferasesignal with the Renilla luciferase signal, and used to represent the“Relative activity of CAR”. The curve-fitting software GraphPad Prism4.0 (Graphpad Software, La Jolla, Calif.) was used to generate the doseresponse curves and determine the IC₅₀ values for tested compounds ifapplicable.

f. Human Vitamin D Receptor (hVDR) Transactivation Assays

Human vitamin D receptor (hVDR) transactivation assays were performedusing VDR-UAS-bla HEK 293T cells (VDR cells, Invitrogen, Carlsbad,Calif.). Cells were maintained by following manufacturer's instruction.Briefly, VDR cells were maintained in matrigel-coated tissue cultureflasks in DMEM supplemented with 10% dialyzed FBS, 0.1 mM non-essentialamino acids, 1 mM sodium pyruvate, 25 mM HEPES, 80 μg/ml of hygromycinB, 80 μg/ml of zeocin, 100 units/ml penicillin and 100 μg/mlstreptomycin. For VDR transactivation assay, various concentrations ofVDR agonist 1α, 25-dihydroxyvitamin D3, various concentrations oftesting compounds alone or combined with 2 nM of 1α, 25-dihydroxyvitaminD3, was added to the wells of black 384-well tissue culture-treatedclear bottom plates with VDR cells (20,000 cells/well) in 30 μl of assaymedium (phenol red-free DMEM supplemented with 2%charcoal/dextran-treated FBS, 0.1 mM non-essential amino acids, 1 mMsodium pyruvate, 100 units/ml penicillin and 100 μg/ml streptomycin).Assay medium containing DMSO without cells serves as background control.24 h later, 6 μl/well of loading solution was added, followed by 90minutes of incubation at room temperature in the dark before measuringthe fluorescent emission at 460 and 535 nm (using excitation at 400 nm)with an Envision plate reader by using the bottom read mode. Aftersubtraction of background, emission signal at 460 and 535 nm was used todetermine the ratio of 460 nm/535 nm, and used to represent the activityof the “Relative activity of VDR”. In the agonistic VDR assay, 100 nM1α, 25-dihydroxyvitamin D3 and DMSO were used as positive (100%activation) and negative (0% activation) controls, respectively. In theantagonistic VDR assay, 2 nM 1α, 25-dihydroxyvitamin D3 and DMSO wereused as corresponding negative (0% inhibition) and positive (100%inhibition) controls. The activities of individual chemicals tested atvarious concentrations were normalized to the corresponding positive andnegative controls to generate % Activation in agonistic assays and %Inhibition in antagonistic assays. The curve-fitting software GraphPadPrism 4.0 (Graphpad Software, La Jolla, Calif.) was used to generate thedose response curves and determine the EC₅₀ (for agonists) or IC₅₀ (forantagonists) values for individually tested compounds if applicable. Inthe VDR assay, la, 25-dihydroxyvitamin D3 had an EC₅₀ of 0.4 nM.

g. Human Glucocorticoid Receptor (hGR) Transactivation Assays

Human glucocorticoid receptor (hGR) transactivation assays wereperformed using GR-UAS-bla HEK 293T cells (hGR cells, Invitrogen,Carlsbad, Calif.). Cells were maintained by following manufacturer'sinstruction. Briefly, hGR cells were maintained in matrigel-coatedtissue culture flasks in DMEM supplemented with 10% dialyzed FBS, 0.1 mMnon-essential amino acids, 25 mM HEPES, 150 μg/ml of hygromycin B, 80μg/ml of zeocin, 100 units/ml penicillin and 100 μg/ml streptomycin. ForGR transactivation assay, various concentrations of GR agonistdexamethasone, GR antagonist mifepristone, various concentrations oftesting compounds alone or combined with 5 nM of dexamethasone, wasadded to the wells of black 384-well tissue culture-treated clear bottomplates with GR cells (20,000 cells/well) in 30 μl of assay medium(phenol red-free DMEM supplemented with 2% charcoal/dextran-treated FBS,0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 25 mM HEPES (pH7.3), 100 units/ml penicillin and 100 μg/ml streptomycin). Assay mediumcontaining DMSO without cells serves as background control. 24 h later,6 μl/well of loading solution was added, followed by 120 minutes ofincubation at room temperature in the dark before measuring thefluorescent emission at 460 and 535 nm (using excitation at 400 nm) withan Envision plate reader by using the bottom read mode. Aftersubtraction of background, emission signal at 460 and 535 nm was used todetermine the ratio of 460 nm/535 nm, and used to represent the activityof the “Relative activity of GR”. In the agonistic GR assay, 100 nMdexamethasone and DMSO were served as positive (100% activation) andnegative (0% activation) controls, respectively. In the antagonistic GRassay, 5 nM dexamethasone and 5 nM dexamethasone along with 100 nMmifepristone were used as corresponding negative (0% inhibition) andpositive (100% inhibition) controls. The activities of individualchemicals tested at various concentrations were normalized to thecorresponding positive and negative controls to generate % Activation inagonistic assays and % Inhibition in antagonistic assays. Thecurve-fitting software GraphPad Prism 4.0 (Graphpad Software, La Jolla,Calif.) was used to generate the dose response curves and determine theEC₅₀ (for agonists) or IC₅₀ (for antagonists) values for individuallytested compounds if applicable. In the GR agonistic assay, dexamethasonehad an EC₅₀ of 2.2 nM. In the GR antagonistic assay, mifepristone had anIC₅₀ of 6.8 nM.

h. Human Retinoid X Receptor Alpha (hRXRa) Transactivation Assays

Human retinoid X receptor alpha (hRXRα) transactivation assays wereperformed using RXR alpha-UAS-bla HEK 293T cells (RXRα cells,Invitrogen, Carlsbad, Calif.). Cells were maintained by followingmanufacturer's instruction. Briefly, RXRα cells were maintained in DMEMsupplemented with 10% dialyzed FBS, 0.1 mM non-essential amino acids, 25mM HEPES, 100 μg/ml of hygromycin B, 100 μg/ml of zeocin, 100 units/mlpenicillin and 100 μg/ml streptomycin. For RXRα transactivation assay,various concentrations of RXRα agonist 9-cis-retinoic acid, variousconcentrations of testing compounds alone or combined with 100 nM of9-cis-retinoic acid, was added to the wells of black 384-well tissueculture-treated clear bottom plates with RXRα cells (20,000 cells/well)in 30 μl of assay medium (phenol red-free DMEM supplemented with 2%charcoal/dextran-treated FBS, 0.1 mM non-essential amino acids, 1 mMsodium pyruvate, 100 units/ml penicillin and 100 μg/ml streptomycin).Assay medium containing DMSO without cells serves as background control.24 h later, 6 μl/well of loading solution was added, followed by 75minutes of incubation at room temperature in the dark before measuringthe fluorescent emission at 460 and 535 nm (using excitation at 400 nm)with an Envision plate reader by using the bottom read mode. Aftersubtraction of background, emission signal at 460 and 535 nm was used todetermine the ratio of 460 nm/535 nm, and used to represent the activityof the “Relative activity of RXRα”. In the agonistic RXRα assay, 10 μM9-cis-retinoic acid and DMSO were used as positive (100% activation) andnegative (0% activation) controls, respectively. In the antagonisticRXRα assay, 100 nM 9-cis-retinoic acid and DMSO were used ascorresponding negative (0% inhibition) and positive (100% inhibition)controls. The activities of individual chemicals tested at variousconcentrations were normalized to the corresponding positive andnegative controls to generate % Activation in agonistic assays and %Inhibition in antagonistic assays. The curve-fitting software GraphPadPrism 4.0 (Graphpad Software, La Jolla, Calif.) was used to generate thedose response curves and determine the EC₅₀ (for agonists) or IC₅₀ (forantagonists) values for individually tested compounds if applicable. Inthe RXRα assay, 9-cis-retinoic acid had an EC₅₀ of 13.3 nM.

i. Human Retinoid X Receptor Beta (hRXTb) Transactivation Assays

Human retinoid X receptor beta (hRXRβ) transactivation assays wereperformed using RXR beta-UAS-bla HEK 293T cells (RXRβ cells, Invitrogen,Carlsbad, Calif.). Cells were maintained by following manufacturer'sinstruction. Briefly, RXRβ cells were maintained in DMEM supplementedwith 10% dialyzed FBS, 0.1 mM non-essential amino acids, 25 mM HEPES,100 μg/ml of hygromycin B, 100 μg/ml of zeocin, 100 units/ml penicillinand 100 μg/ml streptomycin. For RXRβ transactivation assay, variousconcentrations of RXRβ agonist 9-cis-retinoic acid, variousconcentrations of testing compounds alone or combined with 100 nM of9-cis-retinoic acid, was added to the wells of black 384-well tissueculture-treated clear bottom plates with RXRβ cells (25,000 cells/well)in 30 μl of assay medium (phenol red-free DMEM supplemented with 2%charcoal/dextran-treated FBS, 0.1 mM non-essential amino acids, 1 mMsodium pyruvate, 100 units/ml penicillin and 100 μg/ml streptomycin).Assay medium containing DMSO without cells serves as background control.24 h later, 6 μl/well of loading solution was added, followed by 90minutes of incubation at room temperature in the dark before measuringthe fluorescent emission at 460 and 535 nm (using excitation at 400 nm)with an Envision plate reader by using the bottom read mode. Aftersubtraction of background, emission signal at 460 and 535 nm was used todetermine the ratio of 460 nm/535 nm, and used to represent the activityof the “Relative activity of RXRβ”. In the agonistic RXRβ assay, 10 μM9-cis-retinoic acid and DMSO were used as positive (100% activation) andnegative (0% activation) controls, respectively. In the antagonisticRXRβ assay, 100 nM 9-cis-retinoic acid and DMSO were used ascorresponding negative (0% inhibition) and positive (100% inhibition)controls. The activities of individual chemicals tested at variousconcentrations were normalized to the corresponding positive andnegative controls to generate % Activation in agonistic assays and %Inhibition in antagonistic assays. The curve-fitting software GraphPadPrism 4.0 (Graphpad Software, La Jolla, Calif.) was used to generate thedose response curves and determine the EC₅₀ (for agonists) or IC₅₀ (forantagonists) values for individually tested compounds if applicable. Inthe RXRα assay, 9-cis-retinoic acid had an EC₅₀ of 7.6 nM.

j. Human Farnesoid X Receptor (hFXR) Transactivation Assays

Human Farnesoid X receptor (hFXR) transactivation assays were performedusing FXR-UAS-bla HEK 293T cells (FXR cells, Invitrogen, Carlsbad,Calif.). Cells were maintained by following manufacturer's instruction.Briefly, FXR cells were maintained in DMEM supplemented with 10%dialyzed FBS, 0.1 mM non-essential amino acids, 25 mM HEPES, 100 μg/mlof hygromycin B, 100 μg/ml of zeocin, 100 units/ml penicillin and 100μg/ml streptomycin. For FXR transactivation assay, variousconcentrations of FXR agonist GW4604, various concentrations of testingcompounds alone or combined with 200 nM of GW4604, was added to thewells of black 384-well tissue culture-treated clear bottom plates withFXR cells (22,500 cells/well) in 30 μl of assay medium (phenol red-freeDMEM supplemented with 2% charcoal/dextran-treated FBS, 0.1 mMnon-essential amino acids, 1 mM sodium pyruvate, 100 units/ml penicillinand 100 μg/ml streptomycin). Assay medium containing DMSO without cellsserves as background control. 24 h later, 6 μl/well of loading solutionwas added, followed by 90 minutes of incubation at room temperature inthe dark before measuring the fluorescent emission at 460 and 535 nm(using excitation at 400 nm) with an Envision plate reader by using thebottom read mode. After subtraction of background, emission signal at460 and 535 nm was used to determine the ratio of 460 nm/535 nm, andused to represent the activity of the “Relative activity of FXR”. In theagonistic FXR assay, 10 μM GW4604 and DMSO were used as positive (100%activation) and negative (0% activation) controls, respectively. In theantagonistic FXR assay, 200 nM GW4604 and DMSO were used ascorresponding negative (0% inhibition) and positive (100% inhibition)controls. The activities of individual chemicals tested at variousconcentrations were normalized to the corresponding positive andnegative controls to generate % Activation in agonistic assays and %Inhibition in antagonistic assays. The curve-fitting software GraphPadPrism 4.0 (Graphpad Software, La Jolla, Calif.) was used to generate thedose response curves and determine the EC₅₀ (for agonists) or IC₅₀ (forantagonists) values for individually tested compounds if applicable. Inthe FXR assay, GW4604 had an EC₅₀ of 77.1 nM.

k. Human Liver X Receptor Alpha (hLXRa) Transactivation Assays

Human Liver X receptor alpha (hLXRα) transactivation assays wereperformed using LXR alpha-UAS-bla HEK 293T cells (LXRα cells,Invitrogen, Carlsbad, Calif.). Cells were maintained by followingmanufacturer's instruction. Briefly, LXRα cells were maintained in DMEMsupplemented with 10% dialyzed FBS, 0.1 mM non-essential amino acids, 25mM HEPES, 80 μg/ml of hygromycin B, 80 μg/ml of zeocin, 100 units/mlpenicillin and 100 μg/ml streptomycin. For LXRα transactivation assay,various concentrations of LXRα agonist T0901317, various concentrationsof testing compounds alone or combined with 300 nM of T0901317, wasadded to the wells of poly-D-lysine coated black 384-well tissueculture-treated clear bottom plates with LXRα cells (20,000 cells/well)in 30 μl of assay medium (phenol red-free DMEM supplemented with 2%charcoal/dextran-treated FBS, 0.1 mM non-essential amino acids, 1 mMsodium pyruvate, 100 units/ml penicillin and 100 μg/ml streptomycin).Assay medium containing DMSO without cells serves as background control.24 h later, 6 μl/well of loading solution was added, followed by 90minutes of incubation at room temperature in the dark before measuringthe fluorescent emission at 460 and 535 nm (using excitation at 400 nm)with an Envision plate reader by using the bottom read mode. Aftersubtraction of background, emission signal at 460 and 535 nm was used todetermine the ratio of 460 nm/535 nm, and used to represent the activityof the “Relative activity of LXR”. In the agonistic LXRα assay, 2 μMT0901317 and DMSO were used as positive (100% activation) and negative(0% activation) controls, respectively. In the antagonistic LXRα assay,300 nM T0901317 and DMSO were served as corresponding negative (0%inhibition) and positive (100% inhibition) controls. The activities ofindividual chemicals tested at various concentrations were normalized tothe corresponding positive and negative controls to generate %Activation in agonistic assays and % Inhibition in antagonistic assays.The curve-fitting software GraphPad Prism 4.0 (Graphpad Software, LaJolla, Calif.) was used to generate the dose response curves anddetermine the EC₅₀ (for agonists) or IC₅₀ (for antagonists) values forindividually tested compounds if applicable. In the LXRα assay, T0901317had an EC₅₀ of 21.3 nM.

l. Human Liver X Receptor Beta (hLXRb) Transactivation Assays

Human Liver X receptor beta (hLXRβ) transactivation assays wereperformed using LXR beta-UAS-bla HEK 293T cells (LXRβ cells, Invitrogen,Carlsbad, Calif.). Cells were maintained by following manufacturer'sinstruction. Briefly, LXRβ cells were maintained in matrigel-coatedtissue culture flasks in DMEM supplemented with 10% dialyzed FBS, 0.1 mMnon-essential amino acids, 1 mM sodium pyruvate, 25 mM HEPES, 80 μg/mlof hygromycin B, 15 μg/ml of blasticidin, 100 units/ml penicillin and100 μg/ml streptomycin. For LXRβ transactivation assay, variousconcentrations of LXRβ agonist T0901317, various concentrations oftesting compounds alone or combined with 3 μM of T0901317, was added tothe wells of poly-D-lysine coated black 384-well tissue culture-treatedclear bottom plates with LXRβ cells (20,000 cells/well) in 30 μl ofassay medium (phenol red-free DMEM supplemented with 2%charcoal/dextran-treated FBS, 0.1 mM non-essential amino acids, 1 mMsodium pyruvate, 100 units/ml penicillin and 100 μg/ml streptomycin).Assay medium containing DMSO without cells serves as background control.24 h later, 6 μl/well of loading solution was added, followed by 90minutes of incubation at room temperature in the dark before measuringthe fluorescent emission at 460 and 535 nm (using excitation at 400 nm)with an Envision plate reader by using the bottom read mode. Aftersubtraction of background, emission signal at 460 and 535 nm was used todetermine the ratio of 460 nm/535 nm, and used to represent the activityof the “Relative activity of LXRβ”. In the agonistic LXRβ assay, 20 μMT0901317 and DMSO were used as positive (100% activation) and negative(0% activation) controls, respectively. In the antagonistic LXRβ assay,3 μM T0901317 and DMSO were used as corresponding negative (0%inhibition) and positive (100% inhibition) controls. The activities ofindividual chemicals tested at various concentrations were normalized tothe corresponding positive and negative controls to generate %Activation in agonistic assays and % Inhibition in antagonistic assays.The curve-fitting software GraphPad Prism 4.0 (Graphpad Software, LaJolla, Calif.) was used to generate the dose response curves anddetermine the EC₅₀ (for agonists) or IC₅₀ (for antagonists) values forindividually tested compounds if applicable. In the LXRβ assay, T0901317had an EC₅₀ of 50.4 nM.

m. Human Peroxisome Proliferator-Activated Receptor Gamma (PPARΓ)Transactivation Assays

Human peroxisome proliferator-activated receptor gamma (PPARγ)transactivation assays were performed using PPAR gamma-UAS-bla 293Hcells (PPARγ cells, Invitrogen, Carlsbad, Calif.). Cells were maintainedby following manufacturer's instruction. Briefly, PPARγ cells weremaintained in matrigel-coated tissue culture flasks in DMEM supplementedwith 10% dialyzed FBS, 0.1 mM non-essential amino acids, 1 mM sodiumpyruvate, 25 mM HEPES, 100 μg/ml of hygromycin B, 500 μg/ml ofgeneticin, 100 units/ml penicillin and 100 μg/ml streptomycin. For PPARγtransactivation assay, various concentrations of PPARγ agonistrosiglitazone, antagonist GW9662, various concentrations of testingcompounds alone or combined with 100 nM of rosiglitazone, was added tothe wells of poly-D-lysine coated black 384-well tissue culture-treatedclear bottom plates with PPARγ cells (25,000 cells/well) in 30 μl ofassay medium (phenol red-free DMEM supplemented with 2%charcoal/dextran-treated FBS, 0.1 mM non-essential amino acids, 1 mMsodium pyruvate, 100 units/ml penicillin and 100 μg/ml streptomycin).Assay medium containing DMSO without cells serves as background control.24 h later, 6 μl/well of loading solution was added, followed by 120minutes of incubation at room temperature in the dark before measuringthe fluorescent emission at 460 and 535 nm (using excitation at 400 nm)with an Envision plate reader by using the bottom read mode. Aftersubtraction of background, emission signal at 460 and 535 nm was used todetermine the ratio of 460 nm/535 nm, and used to represent the activityof the “Relative activity of PPARγ”. In the agonistic PPARγ assay, 2.5μM rosiglitazone and DMSO were used as positive (100% activation) andnegative (0% activation) controls, respectively. In the antagonisticPPARγ assay, 100 nM rosiglitazone and 1 μM GW9662 along with 100 nMrosiglitazone were used as corresponding negative (0% inhibition) andpositive (100% inhibition) controls. The activities of individualchemicals tested at various concentrations were normalized to thecorresponding positive and negative controls to generate % Activation inagonistic assays and % Inhibition in antagonistic assays. Thecurve-fitting software GraphPad Prism 4.0 (Graphpad Software, La Jolla,Calif.) was used to generate the dose response curves and determine theEC₅₀ (for agonists) or IC₅₀ (for antagonists) values for individuallytested compounds if applicable. In the PPARγ agonistic assay,rosiglitazone had an EC₅₀ of 5.0 nM. In the PPARγ antagonistic assay,GW9662 had an IC₅₀ of 240.8 nM.

4. Biological Characterization of Exemplary Compounds

The compounds in Table 1 below were synthesized and the indicated assayswere carried out as described herein. The assays in Table 2 refer to thecompound numbers used in Table 1, and the assays were carried out asdescribed herein.

TABLE 1 IC₅₀ IC₅₀ EC₅₀ IC₅₀ No. Structure (binding)* (antag)* (agon)*(cyto)* LC-1 

0.41 μM 0.51 μM NA** NA LC-2 

0.99 μM 0.66 μM NA NA LC-3 

0.77 μM 0.52 μM NA NA LC-4 

1.18 μM 0.63 μM NA NA LC-5 

0.64 μM 0.08 μM NA NA LC-6 

1.05 μM 0.39 μM NA NA LC-7 

0.38 μM 0.13 μM NA NA LC-8 

0.01 μM 1.52 μM NA NA LC-9 

0.39 μM NA  0.84 μM NA LC-10

0.08 μM NA  0.75 μM NA LC-11

0.11 μM NA  0.88 μM NA LC-12

0.10 μM NA  0.78 μM NA LC-13

0.07 μM NA  0.84 μM NA LC-14

0.10 μM NA 7.2 μM NA LC-15

10.9 μM  NA 3.8 μM NA LC-16

0.38 μM NA 1.2 μM NA LC-17

0.03 μM NA 1.3 μM NA LC-18

0.03 μM 0.64 μM NA NA LC-19

0.12 μM 1.8 μM  NA NA LC-20

0.01 μM NA 0.91 μM NA LC-21

0.15 μM 0.99 μM NA NA LC-22

0.24 μM NA 0.75 μM NA LC-23

0.10 μM NA 0.73 μM NA LC-24

0.34 μM NA 0.88 μM NA LC-25

0.10 μM NA 1.7 μM NA LC-26

0.07 μM NA  0.16 μM  3.4 μM LC-27

0.09 μM NA 1.9 μM NA LC-28

0.87 μM 0.61 μM NA NA LC-29

0.02 μM NA  0.53 μM NA LC-30

0.01 μM 1.3 μM  NA NA LC-31

0.11 μM NA  0.76 μM 14.8 μM LC-32

2.20 μM NA 3.4 μM NA LC-33

0.85 μM NA 1.2 μM NA LC-34

0.39 μM NA 1.6 μM NA LC-35

0.01 μM NA 1.3 μM  7.2 μM LC-36

0.01 μM NA 2.4 μM NA LC-37

0.69 μM NA 4.1 μM NA LC-38

0.30 μM NA 1.3 μM NA LC-39

0.29 μM NA 1.0 μM 16.1 μM LC-40

0.10 μM 0.52 μM NA NA LC-41

0.99 μM 0.67 μM NA NA LC-42

0.06 μM 0.93 μM NA NA LC-43

8.1 μM  NA 1.5 μM NA LC-44

5.9 μM  NA 1.2 μM 22.5 μM LC-45

1.7 μM  NA 1.1 μM 30.7 μM LC-46

0.28 μM NA  0.98 μM NA LC-47

0.91 μM NA  0.73 μM NA LC-48

0.18 μM NA  0.70 μM 33.8 μM LC-49

0.57 μM 0.97 μM NA NA LC-50

0.41 μM NA  0.18 μM NA LC-51

0.16 μM NA  0.14 μM NA LC-52

0.46 μM 1.4 μM  NA NA LC-53

0.91 μM 0.55 μM NA NA LC-54

0.66 μM NA  0.53 μM NA LC-55

0.37 μM 0.21 μM NA NA LC-56

0.91 μM 0.66 μM NA NA LC-57

0.84 μM 0.39 μM NA NA LC-58

0.45 μM 2.4 μM  NA NA LC-59

0.42 μM 1.1 μM  NA NA LC-60

0.54 μM 2.1 μM  NA NA LC-61

0.06 μM 0.25 μM NA NA LC-62

0.22 μM 0.28 μM NA NA LC-63

2.0 μM  0.44 μM NA NA LC-64

1.2 μM  0.52 μM NA  7.9 μM LC-65

1.1 μM  NA 6.1 μM  7.0 μM LC-66

0.48 μM 0.26 μM NA NA LC-67

0.29 μM NA 1.7 μM NA LC-68

86.5 nM  NA 1.5 μM NA LC-69

12.3 nM  NA  0.61 μM NA LC-70

0.51 μM 4.1 μM  NA 15.3 μM LC-71

0.02 μM 13.9 μM  NA 34.9 μM LC-72

0.69 μM 7.6 μM  NA 30.9 μM LC-73

0.02 μM 6.6 μM  NA NA LC-74

0.06 μM 1.7 μM  NA NA LC-75

0.12 μM NA  0.92 μM NA LC-76

0.14 μM NA 2.8 μM NA LC-77

0.07 μM NA  0.79 μM NA LC-78

0.03 μM NA 1.4 μM 24.4 μM LC-79

0.79 μM 3.1 μM  NA NA LC-80

0.69 μM NA 2.4 μM NA LC-81

6.4 μM  NA 1.2 μM NA LC-82

0.04 μM 17.2 μM  NA 18.5 μM LC-83

0.45 μM NA 5.0 μM 16.2 μM LC-84

0.03 μM NA 3.3 μM 20.9 μM LC-85

0.59 μM 3.9 μM  NA NA LC-86

0.24 μM 0.18 μM NA 26.1 μM LC-87

0.04 μM NA 12.0 μM  NA LC-88

0.10 μM NA 1.4 μM 13.0 μM *IC₅₀ (binding) values were determined usingthe time-resolved fluorescence resonance transfer (TR-FRET) hPXRcompetitive binding assay described herein above; IC₅₀ (antag) and EC50(agon) values were determined using the hPXR transactivation assaydescribed herein above; and IC₅₀ (cyto) values were determined using theHepG2 cytotoxicity assay described herein above. **“NA” indicates thatthe compound was not active in the indicated assay.

TABLE 2 No. CAR* VDR* GR* RXRα* RXRβ* LC-1  NA** NA NA NA NA LC-8 NT^(#) NA NA NA NA LC-18 NT NA NA NA NA LC-21 NT NA NA NA NA LC-28 NTNA NA NA NA LC-30 NT NA NA NA NA LC-40 NT NA NA NA NA LC-41 NT NA NA NANA LC-42 NT NA NA NA NA LC-55 NT NA NA NA NA LC-56 NT NA NA NA NA LC-57NT NA NA NA NA LC-58 NT NA NA NA NA LC-61 NT NA NA NA NA LC-62 NT NA NANA NA LC-63 NT NA NA NA NA LC-64 NT  7.3 μM  5.6 μM  5.8 μM  4.1 μM(Anta) (Anta) (Anta) (Anta) LC-66 NT NA NA NA 19.3 μM (Ag†) LC-70 NT NA20.4 μM 16.1 μM NA (Anta†) (Anta) LC-73 NT NA 4.4 μM NA NA (Anta) LC-85NT NA NA NA 31.0 μM (Anta) LC-86 NT 24.2 μM 21.4 μM 20.6 μM 17.9 μM(Anta) (Anta) (Anta) (Anta) No. FXR* LXRα* LXRβ* PPARγ* LC-1  NA** NA NANA LC-8 NA NA NA NA LC-18 NA NA NA NA LC-21 NA NA NA NA LC-28 NA NA NA14.4 μM (Anta) LC-30 NA NA NA NA LC-40 NA NA NA NA LC-41 NA NA NA NALC-42 NA NA NA NA LC-55 NA NA NA NA LC-56 NA NA NA NA LC-57 NA NA NA NALC-58 NA NA NA NA LC-61 NA NA NA 12.8 μM (Anta†) LC-62 NA NA NA 10.5 μM(Anta) LC-63 NA NA NA NA LC-64  6.3 μM  6.5 μM  4.1 μM  1.5 μM (Anta)(Anta) (Anta) (Anta) LC-66 NA NA NA NA LC-70 14.3 μM NA NA 28.3 μM(Anta) (Anta) LC-73 NA NA NA NA LC-85 NA NA NA 12.8 μM (Anta) LC-86 21.9μM 29.8 μM 18.9 μM 11.8 μM (Anta) (Anta) (Anta) (Anta) *CAR indicatesactivity was determined using the hCAR transactivation assay describedherein above: “VDR” indicates activity was determined using the humanvitamin Dreceptor transactivation assay described herein above; “GR”indicates activity was determined using the human glucocorticoidreceptor transactivation assay described herein above; “RXRα” indicatesactivity was determined using the human retinoid Xreceptor alphatransactivation assay described herein above; and “RXRβ” indicatesactivity was determined using the human retinoid X receptor betatransactivation assay described herein above. *FXR indicates activitywas determined using the human famesoid X receptor transactivation assaydescribed herein above; “LXRα” indicates activity was determined usingthe human liver X receptor alpha transactivation assay described hereinabove; “LXRβ” indicates activity was determined using the human liver Xreceptor beta transactivation assay described herein above; and “PPARγ”indicates activity was determined using the human human peroxisomeproliferator-activated receptor transactivation assay described hereinabove. **NA indicates that the compound was not active in the indicatedassay, †Ag indicates the compound exhibited agonism in the indicatedassay; and “Anta” indicates that the compound exhibited antagonism inthe indicated assay.

5. In Vivo Studies

All animal experiments were conducted in accordance with a protocolapproved by the St. Jude Children's Research Hospital InstitutionalAnimal Care and Use Committee. Male C57BL/6 mice (8-15 weeks old,Charles River Laboratories, Wilmington, Mass.) and humanized PXR(hPXR-tg) mice (in house) were housed at 22-23° C. with a 12 hlight/dark cycle and free access to food and water in the St. JudeAnimal Resources Center certified by the American Association forAccreditation of Laboratory Animal Care. All animals within anexperiment were matched for age and body weight.

a. Hydrodynamic Injections, Treatment, and In Vivo Imaging.

In vivo delivery of CYP3A4-luc reporter gene and hPXR gene into mouseliver was performed using the hydrodynamic injection method as described(Liu et al., 1999, Schuetz et al., 2002 and Wang et al., 2013). Briefly,mice were given a rapid (5-10 s) tail vein injection of 25 μg oflinearized CYP3A4-luc plasmid DNA with linearized hPXR plasmid DNA insterile saline in a volume equal to 10% of body weight. Imaging forluciferase activity was performed 2-8 weeks after somatic gene transfer,during which the bioluminescence was stable in the mice. 15 mice weregiven injections of VivoGlo luciferin (150 mg/kg of body weight, i.p.,Promega), anesthetized using 2.5% isoflurane, and imaged 10 min later inthe Xenogen IVIS 200 system (Xenogen) to obtain a basal image. The micewere then received 3 rounds of sequential treatment intraperitoneallywith vehicle control, 10 mg/kg RIF, or 10 mg/kg RIF plus 10 mg/kg RIFplus 150 mg/kg test compound(4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole)every 24 h for 2 days, respectively, with a washout period of 72-hourbetween two rounds of treatment. 10 hours after the last treatment ofeach round, the mice were imaged as described above. Uniform regions ofinterest were drawn around the liver, and total photon flux was analyzedwith Living Image 3.2 software (Xenogen). The induction of CYP3A4-lucreporter activity was calculated using the imaging from the same mouseas follows: induction rate=total photon flux (after treatment)/totalphoton flux (before treatment).

hPXR-tg mice were generated previously (Xie et al., 2000). Five mice ineach group were dosed orally with vehicle control or 10 mg/kg RIF, every24 h for three days. Eight hours after the last dose, the animals wereeuthanized by C02 and liver tissues were harvested. A piece of eachliver was preserved in RNAlater solution (Invitrogen) at 4° C. for mRNAisolation. The remaining tissue was instantly frozen in liquid nitrogenand stored at −80° C. for total protein extraction. 3-5 mice in eachgroup were dosed orally with vehicle control, 10 mg/kg RIF or 10 mg/kgRIF plus 200 mg/kg test compound(4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole;intraperitoneally) every 24 h for three days. Eight hours after the lastdose, the animals were euthanized by C02 and liver tissues wereharvested. A piece of each liver was preserved in RNAlater solution(Invitrogen) at 4° C. for mRNA isolation. The remaining tissue wasinstantly frozen in liquid nitrogen and stored at −80° C. for totalprotein extraction.

b. Loss of Righting Reflex (LORR) Assay.

Mice were intraperitoneally injected with 250 mg/kg of2,2,2-tribromoethanol, which is metabolically cleared only via mouseCYP3A11. After the mice lost their righting reflex, they were placed ontheir backs under a heat lamp. The duration of LORR was measured as thetime from the start of LORR to recovery (i.e., when mice could rightthemselves after being placed on their backs twice within 1 min). Abaseline LORR duration was established for each mouse at theadministered dose of 2,2,2-tribromoethanol. After a 1-wk washout period,each mouse was administered orally with vehicle, 10 mg/kg RIF or 10mg/kg RIF plus 200 mg/kg test compound(4-((4-(tert-butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole;intraperitoneally) every 24 h for three days, and the righting reflexexperiment was repeated at least 8 h after the last treatment. Thepaired Student's t-test was used to compare LORR duration betweenbaseline and after treatment. A P value <0.05 was considered to indicatea significant difference between compared groups.

c. LC-MS/MS Analysis.

Midazolam and 1-OH midazolam were from BD Gentest. Midazolam-D4 maleate(internal standard, IS) was from Cerilliant; Paclitaxel and3′-p-Hydroxypaclitaxel were from Sigma; and 6α-hydroxy Paclitaxel wasfrom Cayman Chemical. 100 μl of reaction medium at each different timepoint was collected and 200 μl of acetonitrile containing IS was added.This solution was then vigorously mixed for 10 min and centrifuged at10,000 rpm for 10 min. Calibration and quality control samples wereprepared. 5 μl of the samples was injected onto a Waters Acquity UPLCBEH C18 column (2.1×50 mm, 1.7 μm), using a Waters Acquity UPLC system.Chromatographic separation was performed by gradient elution at aconstant flow rate of 1 mL/min for 15 min. The gradient consisted of0.1% formic acid water (mobile phase A) and methanol (mobile phase B).The gradient applied was 0.0 min, 90% A-10% B; 1.35 min, 80% A-20% B;1.65 min, 5% A-95% B; and 1.95 min, 10% A-90% B. The eluate was directedto an AB SCIEX Triple Quad™ 6500 System mass spectrometer (AppliedBiosystems Sciex, Foster, Calif.) equipped with an via electrosprayionization source. Mass transitions of m/z 326 to m/z 291 for MDZ, m/z342 to m/z 324 for 1-OH MDZ, m/z 342 to m/z 325 for 4-OH MDZ, and m/z330 to m/z 295 for D4-MDZ were monitored. Ionization was achieved at 3kV and a temperature of 650° C. Nitrogen was applied as curtain,collision and drying gas at 60 psi. Declustering potentials, entrancepotential and collision energy was as follows: 120 V, 12 V and 35 V forMDZ; 70 V, 12 V and 30 V for 1-OH MDZ; and 120 V, 12 V and 37 V for IS.

6. Prophetic Pharmaceutical Composition Examples

“Active ingredient” as used throughout these examples relates to one ormore disclosed compounds or products of disclosed methods of making asdescribed hereinbefore, or a pharmaceutically acceptable salt, solvate,or polymorph thereof. The following examples of the formulation of thecompounds of the present invention in tablets, suspension, injectablesand ointments are prophetic. Typical examples of recipes for theformulation of the invention are as given below.

Various other dosage forms can be applied herein such as a filledgelatin capsule, liquid emulsion/suspension, ointments, suppositories orchewable tablet form employing the disclosed compounds in desired dosageamounts in accordance with the present invention. Various conventionaltechniques for preparing suitable dosage forms can be used to preparethe prophetic pharmaceutical compositions, such as those disclosedherein and in standard reference texts, for example the British and USPharmacopoeias, Remington's Pharmaceutical Sciences (Mack PublishingCo.) and Martindale The Extra Pharmacopoeia (London The PharmaceuticalPress), which is hereby incorporated by reference.

a. Pharmaceutical Composition for Oral Administration

A tablet can be prepared as follows:

Component Amount Active ingredient 10 to 500 mg Lactose 100 mgCrystalline cellulose  60 mg Magnesium stearate 5 Starch (e.g. potatostarch) Amount necessary to yield total weight indicated below Total(per capsule)

Alternatively, about 100 mg of a disclosed compound, 50 mg of lactose(monohydrate), 50 mg of maize starch (native), 10 mg ofpolyvinylpyrrolidone (PVP 25) (e.g. from BASF, Ludwigshafen, Germany)and 2 mg of magnesium stearate are used per tablet. The mixture ofactive component, lactose and starch is granulated with a 5% solution(m/m) of the PVP in water. After drying, the granules are mixed withmagnesium stearate for 5 min. This mixture is molded using a customarytablet press (e.g. tablet format: diameter 8 mm, curvature radius 12mm). The molding force applied is typically about 15 kN.

Alternatively, a disclosed compound can be administered in a suspensionformulated for oral use. For example, about 100-5000 mg of the desireddisclosed compound, 1000 mg of ethanol (96%), 400 mg of xanthan gum, and99 g of water are combined with stirring. A single dose of about 10-500mg of the desired disclosed compound according can be provided by 10 mlof oral suspension.

In these Examples, active ingredient can be replaced with the sameamount of any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds. Insome circumstances it may be desirable to use a capsule, e.g. a filledgelatin capsule, instead of a tablet form. The choice of tablet orcapsule will depend, in part, upon physicochemical characteristics ofthe particular disclosed compound used.

Examples of alternative useful carriers for making oral preparations arelactose, sucrose, starch, talc, magnesium stearate, crystallinecellulose, methyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, carboxymethyl cellulose, glycerin, sodiumalginate, gum arabic, etc. These alternative carriers can be substitutedfor those given above as required for desired dissolution, absorption,and manufacturing characteristics.

The amount of a disclosed compound per tablet for use in apharmaceutical composition for human use is determined from bothtoxicological and pharmacokinetic data obtained in suitable animalmodels, e.g. rat and at least one non-rodent species, and adjusted basedupon human clinical trial data. For example, it could be appropriatethat a disclosed compound is present at a level of about 10 to 1000 mgper tablet dosage unit.

b. Pharmaceutical Composition for Injectable Use

A parenteral composition can be prepared as follows:

Component Amount Active ingredient 10 to 500 mg Sodium carbonate 560 mg*Sodium hydroxide  80 mg* Distilled, sterile water Quantity sufficient toprepare total volume indicated below. Total (per capsule) 10 ml perampule *Amount adjusted as required to maintain physiological pH in thecontext of the amount of active ingredient, and form of activeingredient, e.g. a particular salt form of the active ingredient.

Alternatively, a pharmaceutical composition for intravenous injectioncan be used, with composition comprising about 100-5000 mg of adisclosed compound, 15 g polyethylenglycol 400 and 250 g water in salinewith optionally up to about 15% Cremophor EL, and optionally up to 15%ethyl alcohol, and optionally up to 2 equivalents of a pharmaceuticallysuitable acid such as citric acid or hydrochloric acid are used. Thepreparation of such an injectable composition can be accomplished asfollows: The disclosed compound and the polyethylenglycol 400 aredissolved in the water with stirring. The solution is sterile filtered(pore size 0.22 μm) and filled into heat sterilized infusion bottlesunder aseptic conditions. The infusion bottles are sealed with rubberseals.

In a further example, a pharmaceutical composition for intravenousinjection can be used, with composition comprising about 10-500 mg of adisclosed compound, standard saline solution, optionally with up to 15%by weight of Cremophor EL, and optionally up to 15% by weight of ethylalcohol, and optionally up to 2 equivalents of a pharmaceuticallysuitable acid such as citric acid or hydrochloric acid. Preparation canbe accomplished as follows: a desired disclosed compound is dissolved inthe saline solution with stirring. Optionally Cremophor EL, ethylalcohol or acid are added. The solution is sterile filtered (pore size0.22 μm) and filled into heat sterilized infusion bottles under asepticconditions. The infusion bottles are sealed with rubber seals.

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

The amount of a disclosed compound per ampule for use in apharmaceutical composition for human use is determined from bothtoxicological and pharmacokinetic data obtained in suitable animalmodels, e.g. rat and at least one non-rodent species, and adjusted basedupon human clinical trial data. For example, it could be appropriatethat a disclosed compound is present at a level of about 10 to 1000 mgper tablet dosage unit.

Carriers suitable for parenteral preparations are, for example, water,physiological saline solution, etc. which can be used withtris(hydroxymethyl)aminomethane, sodium carbonate, sodium hydroxide orthe like serving as a solubilizer or pH adjusting agent. The parenteralpreparations contain preferably 50 to 1000 mg of a disclosed compoundper dosage unit.

F. References

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It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A method for modulating pregnane X receptoractivity in a mammal comprising the step of administering to the mammala therapeutically effective amount of at least one compound having astructure represented by a formula:

wherein R¹ is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and—(C1-C6)-OH; wherein R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H, —(C═O)H,—(C═O)-(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ is hydrogen,hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; andwherein R⁴ is methyl; or wherein R¹ is hydroxy, halogen, C1-C6 alkyl,C1-C6 alkoxy, and —(C1-C6)-OH; wherein R² is halogen, cyano, C1-C6alkyl, C1-C6 alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO₂H,—(C═O)H, —(C═O)-(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R³ ishydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; andwherein R⁴ is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)-(C1-C6 alkyl), —(C═O)—O(C1-C6alkyl), —(C1-C6 alkyl)-(C═O)-(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—O(C1-C6alkyl), Ar¹, or Cy¹; wherein Ar¹ is monocyclic aryl or monocyclicheteroaryl substituted with 0, 1, 2, or 3 groups selected from halogen,hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3monohaloalkyl, or C1-C3 polyhaloalkyl; wherein Cy¹ is C3-C8 cycloalkylor C2-C7 heterocycloalkyl substituted with 0, 1, 2, or 3 groups selectedfrom halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl,C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; and wherein R⁵ is hydrogen,halogen, hydroxy, or C1-C3 alkyl; wherein R⁶ is hydrogen, halogen,hydroxy, or C1-C3 alkyl; and wherein R⁷ is C1-C6 alkyl; or apharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the compound is:


3. The method of claim 1, wherein the compound is:


4. The method of claim 1, wherein the mammal is a human.
 5. The methodof claim 1, wherein R¹ is alkoxy and R³ is alkoxy.
 6. The method ofclaim 1, wherein R³ is methoxy.
 7. The method of claim 1, wherein R⁴ ismethyl.
 8. The method of claim 1, wherein R⁷ is tert-butyl.
 9. Themethod of claim 1, wherein R¹ is hydroxy, halogen, methyl, ethyl,methoxy, or ethoxy; wherein R² is fluoro or methyl; wherein R³ ishydroxy, halogen, methyl, ethyl, methoxy, or ethoxy; wherein R⁴ isfluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, —CH₂F,—CH₂Cl, —(C═O)CH₃, or —CH₂(C═O)OCH₃, wherein R⁵ is hydrogen, hydroxy, ormethyl; wherein R⁶ is hydrogen, hydroxy, or methyl; and wherein R⁷ ispropyl, isopropyl, n-butyl, tert-butyl, or sec-butyl.
 10. The method ofclaim 1, wherein the compound has a structure represented by formula:


11. The method of claim 1, wherein the compound has a structurerepresented by formula:


12. The method of claim 1, wherein the compound is selected from:


13. The method of claim 1, wherein the compound is selected from:


14. The method of claim 1, wherein the compound is:


15. The method of claim 1, wherein the compound is: